Aminoheterocyclic derivatives as antithrombotic or anticoagulant agents

ABSTRACT

Compounds of formula (I), wherein G 1  is CH or N; G 2  is CH or N; R 1  is a variety of optional substituents, L 1  is (1-4C)alkylene; T 1  is CH or N; R 2  and R 3  are independently hydrogen or (1-4C)alkyl or are joined to form a ring; X 1  and X 2  represent various linking groups; Ar is phenylene or certain heteroaryl rings and Q represents a variety of aromatic or heterocyclic rings systems, and pharmaceutically acceptable salts thereof are described as useful antithrombotic and anticoagulant agents, and are selective Factor Xa inhibitors. Processes for their preparation and pharmaceutical compositions containing them are also described.

[0001] The invention relates to aminoheterocyclic derivatives andpharmaceutically-acceptable salts thereof, which possess antithromboticand anticoagulant properties and are accordingly useful in methods oftreatment of the human or animal body. The invention also relates toprocesses for the preparation of said aminoheterocyclic derivatives, topharmaceutical compositions containing them and to their use in themanufacture of medicaments for use in the production of anantithrombotic or anticoagulant effect.

[0002] The antithrombotic and anticoagulant effect produced by thecompounds of the invention is believed to be attributable to theirstrong inhibitory effect against the activated coagulation proteaseknown as Factor Xa. Factor Xa is one of a cascade of proteases involvedin the complex process of blood coagulation. The protease known asthrombin is the final protease in the cascade and Factor Xa is thepreceding protease which cleaves prothrombin to generate thrombin.

[0003] Certain compounds are known to possess Factor Xa inhibitoryproperties and the field has been reviewed by R. B. Wallis, CurrentOpinion in Therapeutic Patents, 1993, 1173-1179. Thus it is known thattwo proteins, one known as antistasin and the other known as tickanticoagulant protein (TAP), are specific Factor Xa inhibitors whichpossess antithrombotic properties in various animal models of thromboticdisease.

[0004] It is also known that certain non-peptidic compounds possessFactor Xa inhibitory properties. Of the low molecular weight inhibitorsmentioned in the review by R. B. Wallis, all possessed a strongly basicgroup such as an amidinophenyl or amidinonaphthyl group.

[0005] It is the object of the present invention to provide a new classof agent which lacks the amidino group previously believed to be anessential feature for a Factor Xa inhibitor.

[0006] We have now found that certain amino-substituted heterocyclicderivatives possess Factor Xa inhibitory activity and in particular alsopossess the advantage of being selective Factor Xa inhibitors, that isthe enzyme Factor Xa is inhibited strongly at concentrations of testcompound which do not inhibit or which inhibit to a lesser extent theenzyme thrombin which is also a member of the blood coagulationenzymatic cascade.

[0007] The compounds of the present invention possess activity in thetreatment or prevention of a variety of medical disorders whereanticoagulant therapy is indicated, for example in the treatment orprevention of thrombotic events associated with coronary artery andcerebro-vascular disease. Further examples of such medical disordersinclude various cardiovascular and cerebrovascular conditions such asmyocardial infarction, the formation of atherosclerotic plaques, venousor arterial thrombosis, coagulation syndromes, disseminatedintravascular coagulation, vascular injury including reocclusion andrestenosis following angioplasty and coronary artery bypass surgery,thrombus formation after the application of blood vessel operativetechniques or after general surgery such as hip replacement surgery, theintroduction of artificial heart valves or on the recirculation ofblood, cerebral infarction, cerebral thrombosis, stroke, cerebralembolism, pulmonary embolism, ischaemia and angina (including unstableangina).

[0008] The compounds of the invention are also useful as inhibitors ofblood coagulation in an ex-vivo situation such as, for example, thestorage of whole blood or other biological samples suspected to containFactor Xa and in which coagulation is detrimental.

[0009] According to one aspect of the invention there is provided anaminoheterocyclic derivative of the formula I

[0010] wherein G¹ is CH or N;

[0011] G² is CH or N;

[0012] m is 1 or 2;

[0013] R¹ is hydrogen, halogeno, trifluoromethyl, trifluoromethoxy,cyano, amino, hydroxy, nitro, (1-4C)alkyl, (1-4C)alkoxy,(1-4C)alkylamino or di-(1-4C)alkylamino;

[0014] L¹ is (1-4C)alkylene, (3-6C)cycloalkane-1,2-diyl or(1-3C)alkylene-carbonyl,

[0015] T¹ is CH or N,

[0016] R¹ is hydrogen or (1-4C)alkyl and R³ is hydrogen or (1-4C)alkyl,or R² and R³ together form a (1-4C)alkylene or methylenecarbonyl group,

[0017] and wherein 1 or 2 methylene groups within L¹ or the ring formedwhen R² and R³ are linked optionally bear 1 or 2 substituents selectedfrom carboxy, carbamoyl, (1-4C)alkyl, (1-4C)alkoxycarbonyl,N-(1-4C)alkylcarbamoyl, N,N-di-(1-4C)alkylcarbamoyl,pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl,piperazin-1-ylcarbonyl, 4-(1-4C)alkylpiperazin-1-ylcarbonyl,hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(11C)alkyl, carboxy-(1-4C)alkyl, (1C)alkoxycarbonyl-(1-4C)alkyl, carbamoyl-(1-4C)alkyl,N-(1-4C)alkylcarbamoyl-(1-4C)alkyl,N,N-di-(1-4C)alkylcarbamoyl-(1-4C)alkyl,pyrrolidin-1-ylcarbonyl-(1-4C)alkyl, piperidino-(1-4C)alkyl,morpholino-(1-4C)alkyl, piperazin-1-yl-(1-4C)alkyl and4-(1-4C)alkylpiperazin-1-yl-(1-4C)alkyl,

[0018] and wherein any heterocyclic group in said substituent optionallybears 1 or 2 (1-4C)alkyl substituents, provided that, when T¹ is N, L¹is not optionally substituted methylene and R² and R³ together do notform an optionally substituted methylene group;

[0019] X¹ is a group of the formula SO, SO₂, C(R⁴)₂, CO, C(R⁴)₂O,C(R⁴)₂S, C(R⁴)₂SO, C(R⁴)₂SO₂, COC(R⁴)₂, SOC(R⁴)₂ or SO₂C(R⁴)₂ when T¹ isCH or N, or, in addition, X¹ is a group of the formula O, S, OC(R⁴)₂ orSC(R⁴)₂ when T¹ is CH, and wherein each R⁴ is independently hydrogen or(1-4C)alkyl;

[0020] Ar is phenylene, or a 5- or 6-membered monocyclic heteroaryl ringcontaining up to 3 heteroatoms selected from nitrogen, oxygen andsulphur,

[0021] and wherein said phenylene or heteroaryl ring is optionallysubstituted with 1 or 2 substituents selected from halogeno,trifluoromethyl, trifluoromethoxy, cyano, nitro, (1-4C)alkyl,(2-4C)alkenyl and (2-4C)alkynyl,

[0022] from the substituent Y¹ which is selected from hydroxy, amino,(1-4C)alkoxy, (2-4C)alkenyloxy, (2-4C)alkynyloxy, (1-4C)alkylamino,di-(1-4C)alkylamino, pyrrolidin-1-yl, piperidino, morpholino,thiamorpholino, 1-oxothiamorpholino, 1,1-dioxothiamorpholino,piperazin-1-yl, 4-(1-4C)alkylpiperazin-1-yl, (1-4C)alkylthio,(1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, (24C)alkanoylamino,benzamido, (1-4C)alkanesulphonamido and benzenesulphonamido, from thesubstituent Y²which is selected from carboxy, carbamoyl,(1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl,N,N-di-(1-4C)alkylcarbamoyl, pyrrolidin-1-ylcarbonyl,piperidinocarbonyl, morpholinocarbonyl, thiamorpholinocarbonyl,1-oxothiamorpholinocarbonyl, 1,1-dioxothiamorpholinocarbonyl,piperazin-1-ylcarbonyl, 4-(1-4C)alkylpiperazin-1-ylcarbonyl,(1-4C)alkanesulphonamidocarbonyl, benzenesulphonamidocarbonyl andbenzylsulphonamidocarbonyl,

[0023] from a substituent of the formula -L²-Y¹ wherein L² is(1-4C)alkylene and Y¹ has any of the meanings defined immediatelyhereinbefore, from a substituent of the formula -L²-Y² wherein L² is(1-4C)alkylene and Y² has any of the meanings defined immediatelyhereinbefore, from a substituent of the formula —X³-L²-Y² wherein X³ isa group of the formula CON(R⁵), CON(L²-Y²), C(R⁵)₂O, O, N(R⁵) orN(L²-Y²), L² is (1-4C)alkylene, Y² has any of the meanings definedimmediately hereinbefore and each R⁵ is independently hydrogen or(1-4C)alkyl, and

[0024] from a substituent of the formula —X³-L³-Y¹ wherein X³ is a groupof the formula CON(R⁵), CON(L³-Y¹), C(R⁵)₂O, O, N(R⁵) or N(L³-Y¹), L³ is(2-4C)alkylene, Y¹ has any of the meanings defined immediatelyhereinbefore and each R⁵ is independently hydrogen or (1-4C)alkyl, andwherein any heterocyclic group in said substituent optionally bears 1 or2 substituents selected from carboxy, carbamoyl, (1-4C)alkyl,(1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl andN,N-di-(1-4C)alkylcarbamoyl, and wherein any phenyl group in saidsubstituent optionally bears 1 or 2 substituents selected from halogeno,trifluoromethyl, cyano, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl,(1-4C)alkoxy, (2-4C)alkenyloxy and (2-4C)alkynyloxy;

[0025] X² is a group of the formula S, SO, SO₂, C(R⁶)₂, CO, N(R⁷)SO₂,N(R⁷)CO, C(R⁶)₂S, C(R⁶)₂SO, C(R⁶)₂SO2, C(R⁶)₂—C(R⁶)₂ or C(R⁶)₂CO, or, inaddition, X² is a group of the formula O, SO₂N(R⁷), CON(R⁷) or C(R⁷)₂Owhen Q is other than phenyl-(2-4C)alkenyl or phenyl-(24C)alkynyl andwherein each R⁶ is independently hydrogen or (1-4C)alkyl and R⁷ ishydrogen, (1-4C)alkyl or a group of the formula —X⁴-Q wherein X⁴ is SO₂or CO and Q has any of the meanings defined immediately hereinafter; and

[0026] Q is phenyl, naphthyl, phenyl-(1-4C)alkyl, phenyl-(2-4C)alkenyl,phenyl-(2-4C)alkynyl or a heterocyclic moiety containing up to 4heteroatoms selected from nitrogen, oxygen and sulphur, and Q optionallybears 1, 2 or 3 substituents selected from halogeno, trifluoromethyl,trifluoromethoxy, cyano, hydroxy, amino, nitro,trifluoromethanesulphonyl, carboxy, carbamoyl, (1-4C)alkyl,(2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, (2-4C)alkenyloxy,(2-4C)alkynyloxy, (1-4C)alkylthio, (1-4C)alkylsulphinyl,(1-4C)alkylsulphonyl, (1-4C)alkylamino, di-(1-4C)alkylamino,(1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl,N,N-di-(1-4C)alkylcarbamoyl, (2-4C)alkanoyl, (2-4C)alkanoylamino,hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, carboxy-(1-4C)alkyl,(1-4C)alkoxycarbonyl-(1-4C)alkyl, carbamoyl-(1-4C)alkyl,N-(1-4C)alkylcarbamoyl-(1-4C)alkyl,N,N-di-(1-4C)alkylcarbamoyl-(1-4C)alkyl, phenyl, heteroaryl, phenoxy,phenylthio, phenylsulphinyl, phenylsulphonyl, benzyl, benzoyl,heteroaryloxy, heteroarylthio, heteroarylsulphinyl andheteroarylsulphonyl,

[0027] and wherein said heteroaryl substituent or the heteroaryl groupin a heteroaryl-containing substituent comprises a 5- or 6-memberedmonocyclic heteroaryl ring containing up to 3 heteroatoms selected fromnitrogen, oxygen and sulphur, and wherein said phenyl, heteroaryl,phenoxy, phenylthio, phenylsulphinyl, phenylsulphonyl, heteroaryloxy,heteroarylthio, heteroarylsulphinyl, heteroarylsulphonyl, benzyl orbenzoyl substituent optionally bears 1, 2 or 3 substituents selectedfrom halogeno, trifluoromethyl, cyano, hydroxy, amino, nitro, carboxy,carbamoyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino,di-(1-4C)alkylamino, (1-4C)alkoxycarbdnyl, N-(1-4C)alkylcarbamoyl,N,N-di-(1-4C)alkylcarbamoyl and (2-4C)alkanoylamino;

[0028] or a pharmaceutically-acceptable salt thereof;

[0029] provided that when X¹ is CO and Ar is phenylene which optionallybears 1 or 2 substituents selected from halogeno, trifluoromethyl,(1-4C)alkyl and (1-4C)alkoxy then X² is not N(R⁷)SO₂, N(R⁷)CO, C(R⁶)₂S,C(R⁶)₂SO, C(R⁶)₂SO₂, C(R⁶)₂—C(R⁶)₂, C(R⁶)₂CO or C(R⁶)₂O.

[0030] In this specification the term “alkyl” includes both straight andbranched chain alkyl groups but references to individual alkyl groupssuch as “propyl” are specific for the straight chain version only. Ananalogous convention applies to other generic terms.

[0031] It is to be understood that certain aminoheterocyclic derivativesof the present invention can exist in solvated as well as unsolvatedforms such as, for example, hydrated forms. It is to be understood thatthe invention encompasses all such solvated forms which possess FactorXa inhibitory activity.

[0032] It is further to be understood that, insofar as certain of thecompounds of the formula defined above may exist in optically active orracemic forms by virtue of one or more asymmetric carbon atoms, theinvention encompasses any such optically active or racemic form whichpossesses Factor Xa inhibitory activity. The synthesis of opticallyactive forms may be carried out by standard techniques of organicchemistry well known in the art, for example by synthesis from opticallyactive starting materials or by resolution of a racemic form.

[0033] Suitable values for the generic terms referred to above includethose set out below.

[0034] When m is 2, each R¹ is independently selected from the list ofsubstituents defined hereinbefore.

[0035] A suitable value for R¹ when it is a halogeno group or for ahalogeno substituent on Ar, on a phenyl group within any substituent onAr, on Q or on a phenyl- or heteroaryl-containing substituent on Q is,for example, fluoro, chloro, bromo or iodo.

[0036] A suitable value for R¹ when it is a (1-4C)alkyl group or for a(1-4C)alkyl substituent on Ar, on a heterocyclic or phenyl group withinany substituent on Ar, on Q or on a phenyl- or heteroaryl-containingsubstituent on Q is, for example, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl or tert-butyl.

[0037] A suitable value for R¹ when it is a (1-4C)alkoxy group or for a(1-4C)alkoxy substituent on Ar, on a phenyl group within any substituenton Ar, on Q or on a phenyl- or heteroaryl-containing substituent on Qis, for example, methoxy, ethoxy, propoxy, isopropoxy or butoxy.

[0038] A suitable value for R¹ when it is a (1-4C)alkylamino group orfor a (1-4C)alkylamino substituent on Ar, on Q or on a phenyl- orheteroaryl-containing substituent on Q is, for example, methylamino,ethylamino or propylamino.

[0039] A suitable value for R¹ when it is di-(1-4C)alkylamino or for adi-(1-4C)alkylamino substituent on Ar, on Q or on a phenyl- orheteroaryl-containing substituent on Q is, for example, dimethylamino,N-ethyl-N-methylamino or diethylamino.

[0040] A suitable value for R², R³, R⁴, R⁵, R⁶ or R⁷ when it is(1-4C)alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl orse-butyl.

[0041] A suitable value for a (1-4C)alkylene group formed by R² and R³together is, for example, methylene, ethylene, trimethylene ortetramethylene.

[0042] A suitable value for L¹ when it is (1-4C)alkylene is, forexample, methylene, ethylene, trimethylene or tetramethylene;

[0043] when it is (3-6C)cycloalkane-1,2-diyl is, for example,cyclopropane-1,2-diyl, cyclobutane-1,2-diyl, cyclopentane-1,2-diyl orcyclohexane-1,2-diyl; and when it is (1-3C)alkylene-carbonyl is, forexample, methylenecarbonyl, ethylenecarbonyl or trimethylenecarbonyl.

[0044] A suitable value for a substituent which may be present on 1 or 2methylene groups within L¹ or the ring formed when R¹ and R³ are linkedis, for example, as follows:— for (1-4C)alkyl: methyl, ethyl and propyl;for (1-4C)alkoxycarbonyl: methoxycarbonyl, ethoxy- carbonyl,propoxycarbonyl and tert-butoxycarbonyl; for N-(1-4C)alkylcarbamoyl:N-methylcarbamoyl, N-ethyl- carbamoyl and N-propyl- carbamoyl; forN,N-di-[(1-4C)alkyl]carbamoyl: N,N-dimethylcarbamoyl,N-ethyl-N-methylcarbamoyl and N,N-diethylcarbamoyl; for4-(1-4C)alkylpiperazin-1-ylcarbonyl: 4-methylpiperazin-1- ylcarbonyl and4-ethyl- piperazin-1-ylcarbonyl; for hydroxy-(1-4C)alkyl: hydroxymethyl,1-hydroxy- ethyl, 2-hydroxyethyl and 3-hydroxypropyl; for(1-4C)alkoxy-(1-4C)alkyl: methoxymethyl, ethoxy- methyl,1-methoxymethyl, 2-methoxyethyl, 2-ethoxy- ethyl and 3-methoxypropyl;for carboxy-(1-4C)alkyl: carboxymethyl, 1-carboxy- ethyl, 2-carboxyethyland 3-carboxypropyl; for (1-4C)alkoxycarbonyl-(1-4C)alkyl:methoxycarbonylmethyl, ethoxycarbonylmethyl, tert- butoxycarbonylmethyl,1-methoxycarbonyl ethyl, 1-ethoxycarbonylethyl, 2-methoxycarbonylethyl,2-ethoxycarbonylethyl, 3-methoxycarbonylpropyl and3-ethoxycarbonylpropyl; for carbamoyl-(1-4C)alkyl: carbamoylmethyl,1-carbamoylethyl, 2-carbamoylethyl and 3-carbamoylpropyl; forN-(1-4C)alkylcarbamoyl-(1-4C)alkyl: N-methylcarbamoylmethyl,N-ethylcarbamoylmethyl, N-propylcarbamoylmethyl,1-(N-methylcarbamoyl)ethyl, 1-(N-ethylcarbamoyl)ethyl,2-(N-methylcarbamoyl)ethyl, 2-(N-ethylcarbamoyl)ethyl and 3-(N-methyl-carbamoyl)propyl; for N,N-di-[(1-4C)alkyl]carbamoyl-N,N-dimethylcarbamoyl- (1-4C)alkyl: methyl, N-ethyl-N-methyl-carbamoylmethyl, N,N- diethylcarbamoylmethyl, 1-(N,N-dimethylcarbamoyl)ethyl, 1-(N,N-diethyl- carbamoyl)ethyl, 2-(N,N- dimethylcarbamoyl)ethyl,2-(N,N-diethylcarbamoyl) ethyl and 3-(N,N-dimethyl- carbamoyl)propyl;for pyrrolidin-1-ylcarbonyl-(1-4C)alkyl: pyrrolidin-1-ylcarbonyl-methyl, 1-(pyrrolidin-1- ylcarbonyl)ethyl and 2-(pyrrolidin-1-ylcarbonyl)ethyl; for piperidinocarbonyl-(1-4C)alkyl:piperidinocarbonylmethyl, 1-(piperidinocarbonyl)ethyl and2-(piperidinocarbonyl) ethyl; for morpholinocarbonyl-(1-4C)alkyl:morpholinocarbonylmethyl, 1-(morpholinocarbonyl)ethyl and2-(morpholinocarbonyl) ethyl; for piperazin-1-ylcarbonyl-(1-4C)alkyl:piperazin-1-ylcarbonylmethyl, 1-(piperazin-1-ylcarbonyl) ethyl and2-(piperazin-1- ylcarbonyl)ethyl; for4-(1-4C)alkylpiperazin-1-ylcarbonyl- 4-methylpiperazin-1- (1-4C)alkyl:ylcarbonylmethyl, 4-ethylpiperazin-1- ylcarbonylmethyl, 2-(4-methylpiperazin-1- ylcarbonyl)ethyl and 2-(4- ethylpiperazin-1-ylcarbonyl)ethyl.

[0045] For suitable value for a (1-4C)alkyl group which may be presenton a heterocyclic group in a substituent on L¹ or the ring formed whenR² and R³ are linked is, for example, methyl, ethyl or propyl.

[0046] A suitable value for Ar when it is phenylene is, for example,1,2-, 1,3- or 1,4-phenylene.

[0047] A suitable value for Ar when it is a 5- or 6-membered monocyclicheteroaryl ring containing up to 3 heteroatoms selected from nitrogen,oxygen and sulphur is, for example, furandiyl, thiophenediyl,pyridinediyl, pyrazinediyl, pyrimidinediyl, pyridazinediyl, pyrrolediyl,pyrazolediyl, imidazolediyl, oxazolediyl, isoxazolediyl, thiazolediyl,isothiazolediyl, 1,2,3-triazolediyl, 1,2,4-triazolediyl, oxadiazolediyl,furazandiyl, thiadiazolediyl and 1,3,5-triazinediyl which may beattached through any available position including through any availablenitrogen atom. Convenient values for Ar include 2,4- or 2,5-furandiyl,2,4- or 2,5-thiophenediyl, 2,4-, 2,5-, 2,6- or 3,5-pyridinediyl, 2,4-,2,5- or 4,6-pyrimidinediyl, 1,4-, 2,4-, 2,5-, 4,1- or 5,2-imidazolediyl,2,4- or 2,5-oxazolediyl, 2,4- or 2,5-thiazolediyl, 2,5-oxadiazolediyl,2,5-thiadiazolediyl and 1,3,5-triazine-2,4-diyl.

[0048] A suitable value for L² when it is (1-4C)alkylene is, forexample, methylene, ethylene, trimethylene or tetramethylene; and for L³when it is (2-4C)alkylene is, for example, ethylene, trimethylene ortetramethylene.

[0049] Suitable values for substituents which may be present on Ar, on aheterocyclic or phenyl group within a substituent on Ar, on Q or on aphenyl- or heteroaryl-containing substituent on Q include, for example:—for (2-4C)alkenyl: vinyl and allyl; for (2-4C)alkynyl: ethynyl andprop-2-ynyl; for (2-4C)alkenyloxy: vinyloxy and allyloxy; for(2-4C)alkynyloxy: ethynyloxy and prop-2- ynyloxy; for4-(1-4C)alkylpiperazin-1-yl: 4-methylpiperazin-1-yl and4-ethylpiperazin-1-yl; for (1-4C)alkylthio: methylthio, ethylthio andpropylthio; for (1-4C)alkylsulphinyl: methylsulphinyl, ethylsulphinyland propylsulphinyl; for (1-4C)alkylsulphonyl: methylsulphonyl,ethylsulphonyl and propylsulphonyl; for (2-4C)alkanoylamino: acetamido,propionamido and butyramido; for (1-4C)alkanesulphonamido:methanesulphonamido and ethanesulphonamido; for (1-4C)alkoxycarbonyl:methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl andtert-butoxycarbonyl; for N-(1-4C)alkylcarbamoyl: N-methylcarbamoyl,N-ethylcarbamoyl and N-propylcarbamoyl; forN,N-di-[(1-4C)alkyl]carbamoyl: N,N-dimethylcarbamoyl,N-ethyl-N-methylcarbamoyl and N,N-diethylcarbamoyl; for4-(1-4C)alkylpiperazin-1-ylcarbonyl: 4-methylpiperazin-1- ylcarbonyl and4-ethyl- piperazin-1-ylcarbonyl; for (1-4C)alkanesulphonamidocarbonyl:methanesulphonamido- carbonyl and ethane- sulphonamidocarbonyl; for(2-4C)alkanoyl: acetyl, propionyl and butyryl; for hydroxy-(1-4C)alkyl:hydroxymethyl, 1-hydroxy- ethyl, 2-hydroxyethyl and 3-hydroxypropyl; for(1-4C)alkoxy-(1-4C)alkyl: methoxymethyl, ethoxy- methyl,1-methoxymethyl, 2-methoxyethyl, 2-ethoxy- ethyl and 3-methoxypropyl;for carboxy-(1-4C)alkyl: carboxymethyl, 1-carboxy- ethyl, 2-carboxyethyland 3-carboxypropyl; for (1-4C)alkoxycarbonyl-(1-4C)alkyl:methoxycarbonylmethyl, ethoxycarbonylmethyl, tert-butoxycarbonylmethyl,1-methoxycarbonylethyl, 1-ethoxycarbonylethyl, 2-methoxycarbonylethyl,2-ethoxycarbonylethyl, 3-methoxycarbonylpropyl and3-ethoxycarbonylpropyl; for carbamoyl-(1-4C)alkyl: carbamoylmethyl,1-carbamoylethyl, 2-carbamoylethyl and 3-carbamoylpropyl; forN-(1-4C)alkylcarbarnoyl-(1-4C)alkyl: N-methylcarbamoylmethyl,N-ethylcarbamoylmethyl, N-propylcarbamoylmethyl,1-(N-methylcarbamoyl)ethyl, 1-(N-ethylcarbamoyl)ethyl,2-(N-methylcarbamoyl)ethyl, 2-(N-ethylcarbamoyl)ethyl and3-(N-methylcarbamoyl) propyl; for N,N-di-[(1-4C)alkyl]carbamoyl-N,N-dimethylcarbamoyl- (1-4C)alkyl: methyl, N-ethyl-N-methyl-carbamoylmethyl, N,N- diethylcarbamoylmethyl, 1-(N,N-dimethylcarbamoyl)ethyl, 1-(N,N-diethyl carbamoyl)ethyl, 2-(N,N- dimethylcarbamoyl)ethyl,2-(N,N-diethyl- carbamoyl)ethyl and 3-(N,N-dimethylcarbamoyl) propyl;

[0050] For the avoidance of doubt it is stated that a suitableheterocyclic group in a substituent which may be present on Ar includes,for example, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl and4-(1-4C)alkylpiperazin-1-yl whether directly attached or attached by wayof a linking group as in, for example, pyrrolidin-1-ylcarbonyl.

[0051] A suitable value for Q when it is naphthyl is for example,1-naphthyl or 2-naphthyl; when it is phenyl-(1-4C)alkyl is, for example,benzyl, phenethyl and 3-phenylpropyl, when it is phenyl-(2-4C)alkenylis, for example, styryl, cinnamyl or 3-phenylprop-2-enyl; and when it isphenyl-(2-4C)alkynyl is, for example, 2-phenylethynyl,3-phenylprop-2-ynyl and 3-phenylprop-1-ynyl.

[0052] A suitable value for Q when it is a heterocyclic moietycontaining up to 4 heteroatoms selected from nitrogen, oxygen andsulphur is, for example, a 5- or 6-membered heterocyclic moiety which isa single ring or is fused to one or two benzo rings such as furyl,benzofuranyl, tetrahydrofuryl, chromanyl, thienyl, benzothienyl,pyridyl, piperidinyl, quinolyl, 1,2,3,4-tetrahydroquinolinyl,isoquinolyl, 1,2,3,4-tetrahydroisoquinolinyl, pyrazinyl, piperazinyl,pyrimidinyl, pyridazinyl, quinoxalinyl, quinazolinyl, cinnolinyl,pyrrolyl, pyrrolidinyl, indolyl, indolinyl, imidazolyl, benzimidazolyl,pyrazolyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl,benzothiazolyl, isothiazolyl, morpholinyl, 4H-1,4-benzoxazinyl,4H-1,4-benzothiazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl,furazanyl, thiadiazolyl, tetrazolyl, dibenzofuranyl and dibenzothienyl,which may be attached through any available position including, for anappropriate X² group such as, for example, SO₂, C(R⁶)₂ or CO, throughany available nitrogen atom and which may bear up to three substituentsincluding a substituent on any available nitrogen atom.

[0053] A suitable value for the heteroaryl substituent on Q or theheteroaryl group in a heteroaryl-containing substituent on Q whichcomprises a 5- or 6-membered monocyclic heteroaryl ring containing up to3 heteroatoms selected from oxygen, nitrogen and sulphur is, forexample, furyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, furazanyland thiadiazolyl which may be attached through any available positionincluding through any available nitrogen atom.

[0054] For the avoidance of any doubt it is to be understood that, inthe portion of the structure of formula I which has the formula—N(R²)-L¹-T¹(R³)—X¹—, it is the N atom which is attached to L¹ and it isthe T¹ group which is attached to X¹ i.e. neither of the R² and R³groups are attached to L¹. It is further to be understood that, withinthe structure of formula I, when R² and R³ together form amethylenecarbonyl group, it is the methylene group thereof which isattached to the N atom and the carbonyl group thereof which is attachedto T¹. Similarly when L¹ is a (1-3 C)alkylene-carbonyl group, forexample a methylenecarbonyl group, it is the methylene group thereofwhich is attached to the N atom and the carbonyl group thereof which isattached to T¹.

[0055] It is also to be understood that, within the structure of formulaI, when X¹ is, for example, a group of the formula C(R⁴)₂O, it is the Catom which is attached to T¹ and the O atom which is attached to Ar.Likewise, when X² is, for example, a group of the formula N(R⁷)SO₂, itis the N atom which is attached to Ar and the SO₂ group which isattached to Q. Likewise, when X³ is, for example, a group of the formulaCON(R⁵), it is the CO group which is attached to Ar and the N atom whichis attached to L² or L³ as appropriate. Likewise when X³ is, for examplea group of the formula CON(L²-Y²), it is the L² group which is attachedto the N atom of the CON group.

[0056] A suitable pharmaceutically-acceptable salt of anaminoheterocyclic derivative of the invention is, for example, anacid-addition salt of an aminoheterocyclic derivative of the inventionwhich is sufficiently basic, for example, an acid-addition salt with,for example, an inorganic or organic acid, for example hydrochloric,hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleicacid. In addition a suitable pharmaceutically-acceptable salt of anaminoheterocyclic derivative of the invention which is sufficientlyacidic is an alkali metal salt, for example a sodium or potassium salt,an alkaline earth metal salt, for example a calcium or magnesium salt,an ammonium salt or a salt with an organic base which affords aphysiologically-acceptable cation, for example a salt with methylamine,dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine.

[0057] Particular compounds of the invention include, for example,aminoheterocyclic derivatives of the formula I, orpharmaceutically-acceptable salts thereof, wherein, unless otherwisestated, each of G¹, G², m, R¹, R², R³, L¹, T¹, X¹, Ar, X² and Q has anyof the meanings defined hereinbefore or in this section concerningparticular compounds of the invention:—

[0058] (a) each of G¹ and G² is CH;

[0059] (b) G¹ is CH and G² is N, or G¹ is N and G² is CH;

[0060] (c) m is 1 and R¹ is hydrogen;

[0061] (d) L¹ is (1-4C)alkylene, T¹ is CH or N, and R² and R³ togetherform a (1-4C)alkylene group, and wherein 1 or 2 methylene groups withinL¹ and the ring formed when R¹ and R³ are linked optionally bears 1 or 2(1-4C)alkyl substituents, provided that, when T¹ is N, L¹ is notoptionally substituted methylene and R² and R³ together do not form anoptionally substituted methylene group;

[0062] (e) L¹ is ethylene, T¹ is CH, and R² and R³ together form amethylene or ethylene group;

[0063] (f) L¹ is ethylene, T¹ is N, and R¹ and R³ together form anethylene group;

[0064] (ff) L¹ is ethylene, T¹ is N, and R² and R³ together form anethylene or propylene group;

[0065] (g) L¹ is ethylene, T¹ is CH or N, and R² and R³ together form anethylene group;

[0066] (h) when T¹ is CH or N, X¹ is a group of the formula SO₂, CH₂,CO, CH₂O, CH₂S, CH₂SO₂, COCH₂ or SO₂CH₂, or, when T¹ is CH, X¹ is, inaddition, a group of the formula O, S, OCH₂ or SCH₂;

[0067] (i) when T¹ is CH or N, X¹ is a group of the formula CH₂, CO orCH₂O, or, when T¹ is CH, X¹ is, in addition, a group of the formula O;

[0068] (j) Ar is 1,3-phenylene or 1,4-phenylene which is optionallysubstituted with 1 or 2 substituents selected from halogeno,trifluoromethyl, cyano, (1-4C)alkyl, hydroxy, amino, (1-4C)alkoxy,(1-4C)alkylamino, di-(1-4C)alkylamino, (1-4C)alkylthio,(1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, (2-4C)alkanoylamino,carboxy, carbamoyl, (1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl,N,N-di-(1-4C)alkylcarbamoyl, pyrrolidin-1-ylcarbonyl,piperidinocarbonyl, morpholinocarbonyl, thiamorpholinocarbonyl,1-oxothiamorpholinocarbonyl, 1,1-dioxothiamorpholinocarbonyl,piperazin-1-ylcarbonyl and 4-(1-4C)alkylpiperazin-1-ylcarbonyl;

[0069] (k) Ar is 1,3-phenylene or 1,4-phenylene which is optionallysubstituted with a substituent of the formula -L²-Y¹ or of the formula-L²-Y² wherein L² is (1-4C)alkylene, Y¹ is selected from hydroxy, amino,(1-4C)alkoxy, (1-4C)alkylamino, di-(1-4C)alkylamino, pyrrolidin-1-yl,piperidino, morpholino, piperazin-1-yl, 4-(1-4C)alkylpiperazin-1-yl,(1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl and(2-4C)alkanoylamino, and Y² is selected from carboxy, carbamoyl,(1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl,N,N-di-(1-4C)alkylcarbamoyl, pyrrolidin-1-ylcarbonyl,piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl and4-(1-4C)alkylpiperazin-1-ylcarbonyl;

[0070] (l) Ar is 1,3-phenylene or 1,4-phenylene which is optionallysubstituted with a substituent of the formula —X³-L²-Y² wherein X³ is agroup of the formula CONH, CON(Me), CH₂O or O, L² is methylene, ethyleneor trimethylene and Y² is selected from carboxy, carbamoyl,(1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl,N,N-di-(1-4C)alkylcarbamoyl, pyrrolidin-1-ylcarbonyl,piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl and4-(1-4C)alkylpiperazin-1-yl;

[0071] (m) Ar is 1,3-phenylene or 1,4-phenylene which is optionallysubstituted with a substituent of the formula —X³-L³-Y¹ wherein X³ is agroup of the formula CONH, CH₂O, O or NH, L³ is ethylene or trimethyleneand Y¹ is hydroxy, amino, (1-4C)alkoxy, (1-4C)alkylamino,di-(1-4C)alkylamino, pyrrolidin-1-yl, piperidino, morpholino,piperazin-1-yl, 4-(1-4C)alkylpiperazin-1-yl, (1-4C)alkylthio,(1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl and (2-4C)alkanoylamino;

[0072] (n) X² is a group of the formula SO₂, CH₂, CO, NHSO₂, N(R⁷)SO₂,NHCO, N(R⁷)CO, CH₂SO₂, CH₂CH₂ or CH₂CO wherein R⁷ is (1-4C)alkyl or agroup of the formula —X⁴-Q wherein X⁴ is SO₂ and Q has any of themeanings defined hereinafter in this section of particular compounds ofthe invention;

[0073] (nn) X² is a group of the formula S;

[0074] (o) X² is a group of the formula SO₂ or NHSO₂;

[0075] (p) X² is a group of the formula SO₂;

[0076] (q) X² is a group of the formula NHSO₂;

[0077] (r) Q is phenyl, naphthyl or phenyl-(1-4C)alkyl which optionallybears 1, 2 or 3 substituents selected from hydroxy, halogeno, cyano,trifluoromethyl. (1-4C)alkyl, (1-4C)alkoxy, phenyl, phenoxy, phenylthio,phenylsulphinyl, phenylsulphonyl, benzyl and benzoyl, and wherein thephenyl substituent or the phenyl group in a phenyl-containingsubstituent optionally bears-1 or 2 substituents selected from halogeno,(1-4C)alkyl and (1-4C)alkoxy;

[0078] (s) Q is phenyl which bears a phenyl substituent and optionallybears 1 or 2 substituents selected from hydroxy, halogeno, cyano,trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy, and wherein the phenylsubstituent optionally bears up to 3 substituents selected fromhalogeno, trifluoromethyl, cyano, (1-4C)alkyl and (1-4C)alkoxy;

[0079] (t) Q is phenyl-(1-4C)alkyl, phenyl-(2-4C)alkenyl orphenyl-(2-4C)alkynyl which optionally bears 1, 2 or 3 substituentsselected from halogeno, cyano, trifluoromethyl, (1-4C)alkyl and(1-4C)alkoxy;

[0080] (u) Q is phenyl-(2-4C)alkenyl which optionally bears 1, 2 or 3substituents selected from halogeno, cyano, trifluoromethyl, (1-4C)alkyland (1-4C)alkoxy;

[0081] (v) Q is phenyl or phenyl-(1-4C)alkyl which bears 1 substituentselected from heteroaryl, heteroaryloxy, heteroarylthio,heteroarylsulphinyl and heteroarylsulphonyl, wherein the heteroarylsubstituent or the heteroaryl group in a heteroaryl-containingsubstituent comprises a 5- or 6-membered monocyclic heteroaryl ringcontaining up to 3 heteroatoms selected from nitrogen, oxygen andsulphur, and wherein said heteroaryl or heteroaryl-containingsubstituent optionally bears 1 or 2 substituents selected from halogeno,(1-4C)alkyl and (1-4C)alkoxy;

[0082] (w) Q is phenyl which bears 1 substituent selected fromheteroaryl, heteroaryloxy, heteroarylthio and heteroarylsulphonyl,wherein the heteroaryl substituent or the heteroaryl group in aheteroaryl-containing substituent is selected from thienyl, pyridyl,pyrimidinyl, pyrazolyl, oxazolyl, thiazolyl, 1,2,3-triazolyl and1,2,4-triazolyl, and wherein said heteroaryl or heteroaryl-containingsubstituent optionally bears 1 or 2 substituents selected from halogenoand (1-4C)alkyl;

[0083] (x) Q is naphthyl which optionally bears 1 or 2 substituentsselected from hydroxy, halogeno, cyano, trifluoromethyl, (1-4C)alkyl and(1-4C)alkoxy;

[0084] (y) Q is a heterocyclic moiety containing up to 2 heteroatomsselected from benzofuranyl, quinolyl, tetrahydroquinolyl, isoquinolyl,quinoxalinyl, quinazolinyl, cinnolinyl, indolyl, benzimidazolyl,indazolyl, benzoxazolyl and benzothiazolyl, and Q optionally bears 1 or2 substituents selected from halogeno, cyano, trifluoromethyl,(1-4C)alkyl and (1-4C)alkoxy;

[0085] (z) Q is a heterocyclic moiety containing up to 2 heteroatomsselected from benzofuranyl, quinolyl, tetrahydroquinolyl, isoquinolyl,quinoxalinyl, quinazolinyl, cinnolinyl, indolyl, benzimidazolyl,indazolyl, benzoxazolyl, benzothiazolyl, dibenzofuranyl anddibenzothienyl, and Q optionally bears 1 or 2 substituents selected fromhalogeno, cyano, trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy;

[0086] (aa) Q is a heterocyclic moiety containing up to 4 heteroatomsselected from furyl, thienyl, pyridyl, pyrimidinyl, pyrrolyl,pyrrolidinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl,thiadiazolyl and tetrazolyl, and Q optionally bears 1 or 2 substituentsselected from halogeno, cyano, carboxy, carbamoyl, (1-4C)alkoxycarbonyl,(1-4C)alkyl, (1-4C)alkoxy, N-(1-4C)alkylcarbamoyl andN,N-di-(1-4C)alkylcarbamoyl;

[0087] (bb) Q is a heterocyclic moiety containing up to 2 heteroatomsselected from thienyl, pyridyl, pyrimidinyl, imidazolyl, pyrazolyl,oxazolyl and thiazolyl, and Q optionally bears 1 or 2 substituentsselected from halogeno, (1-4C)alkyl, (1-4C)alkoxy, phenyl, heteroaryl,phenoxy, phenylthio, phenylsulphinyl, phenylsulphonyl, heteroaryloxy,heteroarylthio, heteroarylsulphinyl, heteroarylsulphonyl, benzyl andbenzoyl, wherein the heteroaryl substituent or the heteroaryl group in aheteroaryl-containing substituent is selected from thienyl, pyridyl,pyrimidinyl, pyrazolyl, oxazolyl and thiazolyl, and wherein said phenyl,phenyl-containing, heteroaryl or heteroaryl-containing substituentoptionally bears 1 or 2 substituents selected from halogeno, (1-4C)alkyland (1-4C)alkoxy; or

[0088] (cc) Q is a heterocyclic moiety containing up to 2 heteroatomsselected from thienyl, pyridyl, oxazolyl and thiazolyl, and Q bears asubstituent selected from phenyl, thienyl, pyridyl, pyrimidinyl,oxazolyl and thiazolyl, which substituent optionally bears 1 or 2substituents selected from halogeno, (1-4C)alkyl and (1-4C)alkoxy, and Qoptionally bears a further substituent selected from halogeno and(1-4C)alkyl;

[0089] or a pharmaceutically-acceptable salt thereof;

[0090] provided that when X¹ is CO and Ar is phenylene which optionallybears 1 or 2 substituents selected from halogeno, trifluoromethyl,(1-4C)alkyl and (1-4C)alkoxy then X² is not N(R⁷)SO₂, N(R⁷)CO, C(R⁶)₂S,C(R⁶)₂SO, C(R⁶)₂SO₂, C(R⁶)₂—C(R⁶)₂, C(R⁶)₂CO or C(R⁶)₂O.

[0091] A particular compound of the invention is an aminoheterocyclicderivative of the formula I

[0092] wherein each of G¹ and G² is CH, G¹ is CH and G² is N, or G¹ is Nand G² is CH;

[0093] m is 1 and R¹ is hydrogen;

[0094] L¹ is ethylene, T¹ is CH or N, and R² and R³ are independentlyhydrogen or together form a methylene, ethylene or propylene group;

[0095] when T¹ is CH or N, X¹ is a group of the formula CH₂, CO, CH₂O orSO₂, or, when T¹ is CH, X¹ is, in addition, a group of the formula O;

[0096] Ar is 1,2-phenylene, 1,3-phenylene, 1,4-phenylene or pyridylgroup which is optionally substituted with 1 or 2 substituents selectedfrom fluoro, chloro, bromo, trifluoromethyl, cyano, methyl, hydroxy,amino, methoxy, methylamino, dimethylamino, methylthio, methylsulphinyl,methylsulphonyl, acetamido, carboxy, carbamoyl, methoxycarbonyl,ethoxycarbonyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl,2-(ethylthio)ethylamino-carbonyl, pyrrolidin-1-ylcarbonyl,piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl and4-methylpiperazin-1-ylcarbonyl;

[0097] X² is a group of the formula S, SO₂, CONH, NHSO₂ or N(R⁷)SO₂wherein R⁷ is methyl or a group of the formula —SO₂Q wherein Q has anyof the meanings defined immediately hereinafter; and

[0098] Q is phenyl, styryl, 1,2,3,4-tetrahydroisoquinolinyl, indolyl,4-biphenylyl or 2-naphthyl which optionally bears 1 or 2 substituentsselected from fluoro, chloro, bromo, trifluoromethyl, 4-chlorophenoxy,methyl and methoxy;

[0099] or a pharmaceutically-acceptable salt thereof;

[0100] provided that when X¹ is CO and Ar is 1,2-, 1,3- or 1,4-phenylenewhich optionally bears 1 or. 2 substituents selected from fluoro,chloro, bromo, trifluoromethyl, methyl and methoxy then X² is not NHSO₂or N(R⁷)SO₂ wherein R⁷ is methyl or a group of the formula —SO₂-Qwherein Q has any of the meanings defined immediately hereinbefore.

[0101] A preferred compound of the invention is an aminoheterocyclicderivative of the formula I

[0102] wherein each of G¹ and G² is CH, G¹ is CH and G² is N, or G¹ is Nand G² is CH;

[0103] m is 1 and R¹ is hydrogen;

[0104] L¹ is ethylene, T¹ is CH or N, and R¹ and R¹ together form anethylene group;

[0105] when T¹ is CH or N, X¹ is a group of the formula CH₂, CO or CH₂O,or, when T¹ is CH, X¹ is, in addition, a group of the formula O;

[0106] Ar is 1,3,phenylene or 1,4-phenylene which is optionallysubstituted with 1 or 2 substituents selected from fluoro, chloro,bromo, trifluoromethyl, cyano, methyl, hydroxy, amino, methoxy,methylamino, dimethylamino, methylthio, methylsulphinyl,methylsulphonyl, acetamido, carboxy, carbamoyl, methoxycarbonyl,ethoxycarbonyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl,pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl,piperazin-1-ylcarbonyl and 4-methylpiperazin-1-ylcarbonyl;

[0107] X² is a group of the formula SO₂, NHSO₂ or N(R⁷)SO₂ wherein R⁷ ismethyl or a group of the formula —SO₂Q wherein Q has any of the meaningsdefined immediately hereinafter; and

[0108] Q is phenyl, styryl, 4-biphenylyl or 2-naphthyl which optionallybears 1 or 2 substituents selected from fluoro, chloro, bromo,trifluoromethyl, methyl and methoxy;

[0109] or a pharmaceutically-acceptable salt thereof;

[0110] provided that when X¹ is CO and Ar is 1,3- or 1,4-phenylene whichoptionally bears 1 or 2 substituents selected from fluoro, chloro,bromo, trifluoromethyl, methyl and methoxy then X² is not NHSO₂ orN(R⁷)SO₂ wherein R⁷ is methyl or a group of the formula —SO₂-Q wherein Qhas any of the meanings defined immediately hereinbefore.

[0111] A further preferred compound of the invention is anaminoheterocyclic derivative of the formula I

[0112] wherein each of G¹ and G² is CH, G¹ is CH and G² is N, or G¹ is Nand G² is CH;

[0113] m is 1 and R¹ is hydrogen;

[0114] L¹ is ethylene, T¹ is N, and R² and R³ together form an ethyleneor propylene group;

[0115] X¹ is a group of the formula CO;

[0116] Ar is 1,4-phenylene, 2-carboxy-1,4-phenylene or2-piperidinocarbonyl-1,4-phenylene (with the X¹ group in the 1-positionand the X² group in the 4-position);

[0117] X² is a group of the formula SO₂; and Q is 2-naphthyl, styryl or4-biphenylyl which optionally bears 1 or 2 substituents selected fromfluoro, chloro and bromo;

[0118] or a pharmaceutically-acceptable salt thereof.

[0119] A particularly preferred compound of the invention is anaminoheterocyclic derivative of the formula I

[0120] wherein each of G¹ and G² is CH;

[0121] m is 1 and R¹ is hydrogen;

[0122] L¹ is ethylene, T¹ is N, and R² and R³ together form an ethylenegroup;

[0123] X¹ is a group of the formula CO;

[0124] Ar is 1,4-phenylene, 2-carboxy-1,4-phenylene or2-piperidinocarbonyl-1,4-phenylene (with the X¹ group in the 1-positionand the X² group in the 4-position);

[0125] X² is a group of the formula SO₂; and Q is 2-naphthyl, styryl or4-biphenylyl which optionally bears 1 or 2 substituents selected fromfluoro, chloro and bromo;

[0126] or a pharmaceutically-acceptable salt thereof.

[0127] Specific compounds of the invention include the followingaminoheterocyclic derivative of the formula I:—

[0128]1-[4-(6-chloronaphth-2-ylsulphonyl)benzoyl]4-(4-pyridyl)piperazine,

[0129]1-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]-4-(4-pyridyl)piperazine,

[0130] 1-[4-(2-naphthylsulphonyl)benzoyl]-4-(4-pyridyl)piperazine,

[0131]1-{4-[(E)-4-chlorostyrylsulphonyl]benzoyl}-4-(4-pyridyl)piperazine,

[0132]1-[4-(4′-bromo-4-biphenylylsulphonyl)benzoyl]-4-(4-pyridyl)piperazine,

[0133]1-[4′-chloro-4-biphenylylsulphonyl)benzoyl]-4-(4-pyridyl)piperazine,

[0134] 1-[4-(4-biphenylylsulphonyl)benzoyl]4-(4-pyridyl)piperazine,

[0135]5-(6-chloronaphth-2-ylsulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylcarbonyl]benzoicacid,

[0136]5-(2-naphthylsulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylcarbonyl]benzoicacid,

[0137]5-(4′-bromo-4-biphenylylsulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylcarbonyl]benzoicacid,

[0138]5-[(E)-4-chlorostyrylsulphonyl]-2-[4-(4-pyridyl)piperazin-1-ylcarbonyl]benzoicacid,

[0139]1-{5-(6-bromonaphth-2-ylsulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylcarbonyl]benzoyl}-piperidine,

[0140]1-{5-(6-chloronaphth-2-yisulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylcarbonyl]benzoyl}-piperidine,

[0141]1-{5-(4′-bromo-4-biphenylyisulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylcarbonyl]benzoyl}-piperidine,

[0142]1-{5-[(E)-4-chlorostyrylsulphonyl]-2-[4-(4-pyridyl)piperazin-ylcarbonyl]benzoyl}piperidine,

[0143]4′-bromo-N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-4-biphenylylsulphonamide,

[0144]4-chloro-N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-(E)-styryisulphonamide,

[0145]6-bromo-N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-2-naphthalenesulphonamide,

[0146]N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-4-toluenesulphonamide,

[0147]N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-N-(4-tolylsulphonyl)-4-toluenesulphonamide,

[0148]4-chloro-N-methyl-N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-(E)-styrylsulphonamide,

[0149]4′-bromo-N-methyl-N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-4-biphenylylsulphonamide,

[0150]4′-bromo-N-{4-[-(4-pyridyl)piperidin-4-ylmethoxy]phenyl}-4-biphenylylsulphonamide,

[0151]6-bromo-N-{4-[1-(4-pyridyl)piperidin-4-ylmethoxy]-phenyl}-2-naphthalenesulphonamide,

[0152]4-chloro-N-{4-[1-(4-pyridyl)piperidin-4-ylmethoxy]phenyl}-(E)-styrylsulphonamide,

[0153]4′-bromo-N-(4′-bromo-4-biphenylylsulphonyl)-N-{4-[1-(4-pyridyl)piperidin-4-ylmethoxy]phenyl}-4-biphenylylsulphonamide,

[0154]6-bromo-N-(6-bromonaphth-2-ylsulphonyl)-N-{4-[1-(4-pyridyl)piperidin-4-ylmethoxy]phenyl}-2-naphthalenesulphonamide,

[0155]6-bromo-N-{3-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-2-naphthalenesulphonamide,

[0156] 4-[4-chlorophenylsulphonyl)phenoxy]-1-(4-(pyridyl)piperidine,

[0157]5-(6-bromonaphth-2-ylsulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylcarbonyl]benzoicacid,

[0158]4-(6-bromonaphth-2-ylsulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylcarbonyl]benzoicacid,

[0159]1-[4-(4-(4-chlorophenoxy)phenylaminocarbonyl)benzyl]-4-(4-pyridyl)piperazine,

[0160]6-bromo-N-{2-[1-(4-pyridyl)piperidin-4-ylmethoxy]phenyl)-2-naphthalenesulphonamide,

[0161]4-chloro-N-{3-[1-(4-pyridyl)piperidin-4yloxy]phenyl}-(E)-styrylsulphonamide,

[0162]4-[4-(6-bromonaphth-2-ylsulphonyl)phenoxy]-1-(4-pyridyl)piperidine,

[0163]4-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]-1-(4-pyridyl)piperidine,

[0164] 4-[4-(6-bromonaphth-2-ylthio)benzoyl]-1-(4-pyridyl)piperidine,

[0165]1-[4-(6-bromonaphth-2-ylsulphonyl)phenylsulphonyl]-1-(4-pyridyl)piperazine,

[0166]6-(bromo-2-(4-(2-pyrimidin-4-yl)aminoethylaminocarbonyl)phenylsulphonyl)naphthalene,

[0167] 1-[4-(6-bromonaphth-2-ylthio)benzoyl]-4-(4-pyridyl)piperazine,

[0168]1-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]-4-(4-pyridyl)piperazine,

[0169]1-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]-4-(4-pyrimidinyl)-piperazine,

[0170]1-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]-4-(4-pyridazinyl)piperazine,

[0171]1-[4-(6-bromonaphth-2-ylsulphonyl-2-trifluoromethylbenzoyl]-4-(4-pyridyl)piperazine,

[0172]1-[4-(6-bromonaphth-2-ylthio)-2-trifluoromethylbenzoyl]-4-(4-pyridyl)piperazine,

[0173]1-[4-(6-bromonaphth-2-ylthio)-2-carboxybenzoyl]-4-(4-pyridyl)piperazine

[0174]1-[5-(6-bromonaphth-2-ylthio)-2-carboxybenzoyl]-4-(4-pyridyl)piperazine,

[0175]1-[5-(6-bromonaphth-2-ylsulphonyl)-2-methoxycarbonylbenzoyl]-4-(4-pyridyl)piperazine,

[0176]1-[4-(6-bromonaphth-2-ylsulphonyl)-2-methoxycarbonylbenzoyl]-4-(4-pyridyl)piperazine,

[0177]1-[4-(6-bromonaphth-2-ylsulphonyl)-2-(2-(ethylthio)-ethylaminocarbonyl)benzoyl]-4-(4-pyridyl)piperazine,

[0178]1-[5-(6-bromonaphth-2-ylsulphonyl)-2-(2-ethylthio)ethylaminocarbonyl)benzoyl]-4-(4-pyridyl)piperazine,

[0179]1-[4-(6-bromonaphth-2-ylsulphonyl)-2-(piperidin-1-ylcarbonyl]-4-(4-pyridyl)piperazine,

[0180]1-[5-(6-bromonaphth-2-ylsulphonyl)-2-(piperidin-1-ylcarbonyl]-4-(4-pyridyl)piperazine,

[0181]1-[4-(4-(3-chlorophenyl)piperazin-1-ylsulphonyl)benzoyl]-4-(4-pyridyl)piperazine,

[0182]1-[4-(6-chloro-1,2,3,4-tetrahydroisoquinolin-2-ylsulphonylbenzoyl]-4-(4-pyridyl)piperazine,

[0183]1-(4-pyridyl)-(5-(6-methoxyindol-2-ylcarbonylamino)pyrid-2-yloxy)pyrrolidine,

[0184]1-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]-4-(2-methylpyrid-4-yl)piperazine,

[0185]1-[4-(6-bromonlaphth-2-ylsulphonlyl)benzoyl]-4-(4-pyridyl)hexahydro-1,4-diazepine,

[0186] or a pharmaceutically-acceptable salt thereof.

[0187] An aminoheterocyclic derivative of the formula I, orpharmaceutically-acceptable salt thereof, may be prepared by any processknown to be applicable to the preparation of structurally-relatedcompounds. Such procedures are provided as a further feature of theinvention and are illustrated by the following representative processesin which, unless otherwise stated G¹, G², m, R¹, R², L¹, T¹, R³, X¹, Ar,X² and Q have any of the meanings defined hereinbefore, provided thatwhen there is an amino, alkylamino, hydroxy or carboxy group in R¹, L¹,R², R³, Ar or Q then any such group is protected by a conventionalprotecting group as necessary which may be removed when so desired byconventional means.

[0188] Necessary starting materials may be obtained by standardprocedures of organic chemistry.

[0189] (a) For the production of those compounds of the formula Iwherein T¹ is N and X¹ is CO, the reaction, conveniently in the presenceof a suitable base, of an amine of the formula II

[0190] with an acid of the formula III

HO₂C—Ar—X²-Q  III

[0191] or a reactive derivative thereof.

[0192] A suitable reactive derivative of an acid of the formula III is,for example, an acyl halide, for example an acyl chloride formed by thereaction of the acid and an inorganic acid chloride, for example thionylchloride; a mixed anhydride, for example an anhydride formed by thereaction of the acid with a chloroformate such as isobutyl chloroformateor with an activated ketone such as 1,1′-carbonyldiimidazole; an activeester, for example an ester formed by the reaction of the acid and aphenol such as pentafluorophenol, an ester such as pentafluorophenyltrifluoroacetate or an alcohol such as N-hydroxybenzotriazole orN-hydroxysuccinimide; an acyl azide, for example an azide formed by thereaction of the acid and an azide such as diphenylphosphoryl azide; anacyl cyanide, for example a cyanide formed by the reaction of an acidand a cyanide such as diethylphosphoryl cyanide; or the product of thereaction of the acid and a carbodiimide such asN,N′-dicyclohexylcarbodiimide orN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide.

[0193] The reaction is conveniently carried out in the presence of asuitable base such as, for example, an alkali or alkaline earth metalcarbonate, alkoxide, hydroxide or hydride, for example sodium carbonate,potassium carbonate, sodium ethoxide, potassium butoxide, sodiumhydroxide, potassium hydroxide, sodium hydride or potassium hydride, oran organometallic base such as an alkyl-lithium, for examplen-butyl-lithium, or a dialkylamino-lithium, for example lithiumdi-isopropylamide, or, for example, an organic amine base such as, forexample, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,triethylamine, morpholine or diazabicyclo[5.4.0]undec-7-ene. Thereaction is also preferably carried out in a suitable inert solvent ordiluent, for example methylene chloride, chloroform, carbontetrachloride, tetrahydrofuran, 1,2-dimethoxyethane,N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one,dimethylsulphoxide or acetone, and at a temperature in the range, forexample, −78° to 150° C., conveniently at or near ambient temperature.

[0194] An analogous procedure may be employed for the preparation ofthose compounds of the formula I wherein T¹ is N and X¹ is a group ofthe formula COC(R⁴)₂.

[0195] A suitable protecting group for an amino or alkylamino group is,for example, an acyl group, for example an alkanoyl group such asacetyl, an alkoxycarbonyl group, for example a methoxycarbonyl,ethoxycarbonyl or tert-butoxycarbonyl group, an arylmethoxycarbonylgroup, for example benzyloxycarbonyl, or an aroyl group, for examplebenzoyl. The deprotection conditions for the above protecting groupsnecessarily vary with the choice of protecting group. Thus, for example,an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroylgroup may be removed for example, by hydrolysis with a suitable basesuch as an alkali metal hydroxide, for example lithium or sodiumhydroxide. Alternatively an acyl group such as a tert-butoxycarbonylgroup may be removed, for example, by treatment with a suitable acidsuch as hydrochloric, sulphuric or phosphoric acid or trifluoroaceticacid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl groupmay be removed, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid for example borontris(trifluoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group which may beremoved by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

[0196] A suitable protecting group for a hydroxy group is, for example,an acyl group, for example an alkanoyl group such as acetyl, an aroylgroup, for example benzoyl, or an arylmethyl group, for example benzyl.The deprotection conditions for the above protecting groups willnecessarily vary with the choice of protecting group. Thus, for example,an acyl group such as an alkanoyl or an aroyl group may be removed, forexample, by hydrolysis with a suitable base such as an alkali metalhydroxide, for example lithium or sodium hydroxide. Alternatively anarylmethyl group such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

[0197] A suitable protecting group for a carboxy group is, for example,an esterifying group, for example a methyl or an ethyl group which maybe removed, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a tert-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

[0198] (b) For the production of those compounds of the formula Iwherein T¹ is CH and X¹ is O or C(R⁴)₂O, the reaction, conveniently inthe presence of a suitable coupling agent, of a compound of the formulaIV

[0199] wherein n is 0 or 1 and Z is a displaceable group, with aphenolic compound the formula V

HO—Ar—X²-Q  V

[0200] A suitable value for the displaceable group Z is, for example, ahalogeno or sulphonyloxy group, for example a fluoro, chloro, bromo,mesyloxy or 4-tolylsulphonyloxy group.

[0201] A suitable reagent for the coupling reaction when Z is a halogensor sulphonyloxy group is, for example, a suitable base, for example, analkali or alkaline earth metal carbonate, hydroxide or hydride, forexample sodium carbonate, hydroxide or hydride, for example sodiumcarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide,sodium hydride or potassium hydride. The alkylation reaction ispreferably performed in a suitable inert solvent or diluent, for exampleN,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide,acetone, 1,2-dimethoxyethane or tetrahydrofuran, and at a temperature inthe range, for example, −10° to 150° C., conveniently at or near ambienttemperature.

[0202] A suitable reagent for the coupling reaction of the alcohol ofthe formula IV wherein Z is a hydroxy group is, for example, the reagentobtained when said alcohol is reacted with a di-(1-4C)alkylazodicarboxylate in the presence of a triarylphosphine ortri-(1-4C)alkylphosphine, for example with diethyl azodicarboxylate inthe presence of triphenylphosphine or tributylphosphine. The reaction ispreferably performed in a suitable inert solvent or diluent, for exampleacetone, 1,2-dimethoxyethane or tetrahydrofuran, and at a temperature inthe range, for example, 10° to 80° C., conveniently at or near ambienttemperature.

[0203] An analogous procedure may be employed for the preparation ofthose compounds of the formula I wherein T¹ is CH and X¹ is a group ofthe formula S or C(R⁴)₂S.

[0204] (c) For the production of those compounds of the formula Iwherein T¹ is N and X¹ is CH(R⁴), the reductive amination of a ketocompound of the formula VI

R⁴—CO—Ar—X²-Q  VI

[0205] with an amine of the formula VII

[0206] Any reducing agent known in the art for promoting a reductiveamination reaction may be employed. A suitable reducing agent is, forexample, a hydride reducting agent, for example an alkali metalaluminium hydride such as lithium aluminium hydride or, preferably, analkali metal borohydride such as sodium borohydride, sodiumcyanoborohydride, sodium triethylborohydride, sodiumtrimethoxyborohydride and sodium triacetoxyborohydride. The reaction isconveniently performed in a suitable inert solvent or diluent, forexample tetrahydrofuran and diethyl ether for the more powerful reducingagents such as lithium aluminium hydride, and, for example, methylenechloride or a protic solvent such as methanol and ethanol for the lesspowerful reducing agents such as sodium triacetoxyborohydride. Thereaction is performed at a temperature in the range, for example, 10° to80° C. conveniently at or near ambient temperature.

[0207] (d) For the production of those compounds of the formula Iwherein X² is a group of the formula N(R⁷)SO₂, the reaction,conveniently in the presence of a suitable base as defined hereinbefore,of an amine of the formula VIII

[0208] with a compound of the formula IX

Z-SO₂-Q  IX

[0209] wherein Z is a displaceable group as defined hereinbefore.

[0210] The reaction is conveniently performed in a suitable inertsolvent or diluent as defined hereinbefore and at a temperature in therange, for example, 0° to 150° C., conveniently at or near ambienttemperature.

[0211] An analogous procedure may be employed for those compounds of theformula I wherein X² is a group of the formula N(R⁷)CO.

[0212] (e) For the production of those compounds of the formula Iwherein X² is a group of the formula N(R⁷)SO₂, the reaction,conveniently in the presence of a suitable base as defined hereinbefore,of a sulphonamide of the formula X

[0213] with a compound of the formula XI

R⁷-Z  XI

[0214] wherein Z is a displaceable group as defined hereinbefore.

[0215] The reaction is conveniently performed in a suitable inertsolvent or diluent as defined hereinbefore and at a temperature in therange, for example, 0° to 150° C., conveniently at or near ambienttemperature.

[0216] An analogous procedure may be employed for those compounds of theformula I wherein X² is a group of the formula N(R⁷)CO.

[0217] (f) For the production of those compounds of the formula Iwherein X² is a group of the formula SO₂N(R⁷) the reaction, convenientlyin the presence of a suitable base as defined hereinbefore, of acompound of the formula XII

[0218] wherein Z is a displaceable group as defined hereinbefore, withan amine of the formula XIII

(R⁷)NH-Q  XIII

[0219] The reaction is conveniently performed in a suitable inertsolvent or diluent as defined hereinbefore and at a temperature in therange, for example, 0° to 150° C., conveniently at or near ambienttemperature.

[0220] An analogous procedure may be employed for the preparation ofthose compounds of the formula I wherein X² is a group of the formulaCON(R⁷).

[0221] (g) For the production of those compounds of the formula Iwherein T¹ is CH and X¹ is a group of the formula OC(R⁴)₂, the reactionconveniently in the presence of a suitable coupling agent as definedhereinbefore, of an alcohol of the formula XIV

[0222] with a compound of the formula XV

Z-C(R⁴)₂—Ar—X²-Q  XV

[0223] wherein Z is a displaceable group as defined hereinbefore.

[0224] The reaction is conveniently performed in a suitable inertsolvent or diluent as defined hereinbefore and at a temperature in therange, for example, 0° to 150° C., conveniently at or near ambienttemperature.

[0225] An analogous procedure may be employed for the preparation ofthose compounds of the formula I wherein T¹ is CH and X¹ is a group ofthe formula SC(R⁴)₂.

[0226] (h) For the production of those compounds of the formula Iwherein X² is a group of the formula C(R⁶)₂S, the reaction, convenientlyin the presence of a suitable base as defined hereinbefore, of acompound of the formula XVI

[0227] wherein Z is a displaceable group as defined hereinbefore with athiol of the formula XVII

HS-Q  XVII

[0228] The reaction is conveniently performed in a suitable inertsolvent or diluent as defined hereinbefore and at a temperature in therange, for example, 0° to 150° C., conveniently at or near ambienttemperature.

[0229] (i) For the production of those compounds of the formula Iwherein L¹, R², R³, Ar or Q bears a carboxy or carboxy-containing group,the hydrolysis of a compound of the formula I wherein L¹, R², R³, Ar orQ bears a (1-4C)alkoxycarbonyl group.

[0230] The hydrolysis reaction may conveniently be carried out in aconventional manner using, for example, acidic or basic catalysis. Asuitable acid for the acidic hydrolysis of an ester group is, forexample, an inorganic acid such as hydrochloric or sulphuric acid. Asuitable base for the basic hydrolysis of an ester group is, forexample, an alkali or alkaline earth metal hydroxide such as sodiumhydroxide or potassium hydroxide.

[0231] The reaction is conveniently performed in a suitable solvent ordiluent such as an alcohol, for example methanol or ethanol, and at atemperature in the range, for example 0° to 120° C., conveniently in therange of 15° to 60° C.

[0232] (j) For the production of those compounds of the formula Iwherein L¹, R², R³, Ar or Q bears a carbamoyl, N-alkylcarbamoyl,N,N-dialkylcarbamoyl or other aminocarbonyl group for examplepiperidinocarbonyl or 2-(ethylthio)aminoethylaminocarbonyl, the reactionof a compound of the formula I wherein L¹, R², R³, Ar or Q bears acarboxy group, or a reactive derivative thereof as defined hereinbefore,with ammonia, an alkylamine, dialkylamine or an appropriate aminocompound.

[0233] The reaction is conveniently performed in a suitable inertsolvent or diluent as defined hereinbefore and at a temperature in therange, for example, 0° to 120° C., conveniently in the range 15° to 600.

[0234] Similarly compounds of the formula I bearing ester groups may beprepared by esterification of the corresponding carboxy compound.

[0235] (k) For the production of those compounds of the formula Iwherein X¹ is a group of the formula SO, SO₂, C(R⁴)₂SO, C(R⁴)₂SO₂,SOC(R⁴)₂ or SO₂C(R⁴)₂, wherein Ar bears a (1-4C)alkylsulphinyl,(1-4C)alkylsulphonyl, 1-oxothiamorpholino or 1,1-dioxothiamorpholinogroup or a substituent which contains a (1-4C)alkylsulphinyl,(1-4C)alkylsulphonyl, 1-oxothiamorpholino or 1,1-dioxothiamorpholinogroup, wherein X² is a group of the formula SO, SO₂, C(R⁶)₂SO orC(R⁶)₂SO₂, or wherein Q bears a (1-4C)alkylsulphinyl,(1-4C)alkylsulphonyl, phenylsulphinyl, phenylsulphonyl,heteroarylsulphinyl or heteroarylsulphonyl group, the oxidation of thecorresponding compound of the formula I which contains a thio group. Asuitable oxidising agent is, for example, any agent known in the art forthe oxidation of thio to sulphinyl and/or sulphonyl, for example,hydrogen peroxide, a peracid (such as 3-chloroperoxybenzoic orperoxyacetic acid), an alkali metal peroxysulphate (such as potassiumperoxymonosulphate), chromium trioxide or gaseous oxygen in the presenceof platinum. The oxidation is generally carried out under as mildconditions as possible and with the required stoichiometric amount ofoxidising agent in order to reduce the risk of over oxidation and damageto other functional groups. In general the reaction is carried out in asuitable solvent or diluent such as methylene chloride, chloroform,acetone, tetrahydrofuran or tert-butyl methyl ether and at atemperature, for example, at or near ambient temperature, that is in therange 15 to 35° C. When a compound carrying a sulphinyl group isrequired a milder oxidising agent may also be used, for example sodiumor potassium metaperiodate, conveniently in a polar solvent such asacetic acid or ethanol. It will be appreciated that when a compound ofthe formula I containing a sulphonyl group is required, it may beobtained by oxidation of the corresponding sulphinyl compound as well asof the corresponding thio compound.

[0236] (l) The reaction of an activated derivative of a compound of theformula XVIII:

[0237] wherein L is a displaceable group as hereinbefore defined with acompound of the formula XIX:

NH(R²)-L¹-T¹(R³)—X¹—Ar—X²-Q  XIX

[0238] Typically L is halo for example fluoro or chloro and the reactionis performed in a substantially inert solvent, as hereinbefore defined,at an ambient or elevated temperature, and in the presence of a suitablebase for example an, organic amine such as triethylamine. The compoundsof the formula II-XIX inclusive are useful intermediates in theprocesses for making the compounds of the formula I. In another aspectthe present invention provides novel compounds and classes of compoundwithin the generic formulae II-XIX inclusive.

[0239] The compounds of the formula II-XIX inclusive may be prepared byany process known to be applicable to the preparation of structurallyrelated compounds, for example, where applicable, by methods related tothose described hereinbefore for preparing compounds of the formula I.Particular reference may be made to the methods of the Examplesdescribed hereinafter.

[0240] Intermediates of particular interest include those of the formulaXX and XXI:

 HOOC—Ar—X²-Q  XXI

[0241] and active derivatives thereof, wherein G¹, G², R¹, m, R², L¹,T¹, R, X¹, Ar, X² and Q are as defined in relation to formula I.

[0242] When a pharmaceutically-acceptable salt of a compound of theformula I is required, it may be obtained, for example, by reaction ofsaid compound with a suitable acid or base using a conventionalprocedure.

[0243] When an optically active form of a compound of the formula I isrequired, it may be obtained, for example, by carrying out one of theaforesaid procedures using an optically active starting material or byresolution of a racemic form of said compound using a conventionalprocedure.

[0244] As stated previously, the compounds of the formula I areinhibitors of the enzyme Factor Xa. The effects of this inhibition maybe demonstrated using one or more of the standard procedures set outhereinafter:—

[0245] a) Measurement of Factor Xa Inhibition

[0246] An in vitro assay system was carried out based on the method ofKettner et al., J. Biol. Chem., 1990, 265, 18289-18297, whereby variousconcentrations of a test compound were dissolved in DMSO and diluted ina pH 7.5 buffer containing 0.5% of a polyethylene glycol (PEG 6000) andincubated at 37° C. with human Factor Xa (0.001 Units/ml, 0.3 ml) for 15minutes. The chromogenic substrate S-2765 (KabiVitum AB, 20 μM) wasadded and the mixture was incubated at 37° C. for 20 minutes whilst theabsorbance at 405 nm was measured. The maximum reaction velocity (Vmax)was determined and compared with that of a control sample containing notest compound. Inhibitor potency was expressed as an IC₅₀ value.

[0247] b) Measurement of Thrombin Inhibition

[0248] The procedure of method a) was repeated except that humanthrombin (0.005 Units/ml) and the chromogenic substrate S-2238(KabiVitum AB, 7 μM) were employed.

[0249] c) Measurement of Anticoagulant Activity

[0250] An in vitro assay whereby human, rat or rabbit venous blood wascollected and added directly to a sodium citrate solution (3.2 g/100 ml,9 parts blood to 1 part citrate solution). Blood plasma was prepared bycentrifugation (1000 g, 15 minutes) and stored at 2-4° C. Conventionalprothrombin time (PT) tests were carried out in the presence of variousconcentrations of a test compound and the concentration of test compoundrequired to double the clotting time, hereinafter referred to as CT2,was determined. In the PT test, the test compound and blood plasma wereincubated at 37° C. for 10 minutes. Tissue thromboplastin with calcium(Sigma Limited, Poole, England) was added and fibrin formation and thetime required for a clot to form were determined.

[0251] d) An Ex Vivo Assay of Anticoagulant Activity

[0252] The test compound was administered intravenously or orally to agroup of Alderley Park Wistar rats. At various times thereafter animalswere anaesthetised, blood was collected and PT coagulation assaysanalogous to those described hereinbefore were conducted. In additionthe plasma concentration of compounds is determined by comparison withthe anti-Factor Xa activity of a standard compound.

[0253] e) An In Vivo Measurement of Antithrombotic Activity

[0254] Thrombus formation was induced using an analogous method to thatdescribed by Vogel et al., Thromb. Research, 1989, 54, 399-410. A groupof Alderley Park Wistar rats was anaesthetised and surgery was performedto expose the vena cava. Collateral veins were ligated and two loosesutures were located, 0.7 cm apart, round the inferior vena cava. Testcompound was administered intravenously or orally. At an appropriatetime thereafter tissue thromboplastin (30 μl/kg) was administered viathe jugular vein and, after 10 seconds, the two sutures were tightenedto induce stasis within the ligated portion of vena cava. After 10minutes the ligated tissue was excised and the thrombus therein wasisolated, blotted and weighed.

[0255] f) An In Vivo Measurement of Antithrombotic Activity

[0256] Using a method similar to that of Smith J R et al Br. J.Pharmacol. 1982, 77: 29-38, fasted male Alderley Park rats (360-410 g)are pre-dosed at various times by oral (5 ml/kg) or subcutaneous (1ml/kg) routes before being anaesthetised with Intraval (120 mg/kg i.p.).The left jugular vein and the right carotid artery are exposed andcannulated with a polypropylene catheters 12 cm in length. Anarterio-venous shunt is completed by connecting the two catheters with a6 cm length of tubing (i.d. 0.3 cm) which contains a 5 cm length ofpre-weighed cotton. All tubes were filled with saline prior to theestablishment of the circuit. Clamps are removed from the catheters andblood is allowed to flow through the polypropylene tubing for 20 mins.During this time the effect of the test compound on template bleedingtime is assessed. The shunt is then closed and the thrombus which hasdeveloped on the cotton thread is removed, blotted dry and weighed.Blood samples are also taken at this point by cardiac puncture into 3.2%tri-sodium citrate, plasma is prepared by centrifugation (5 mins 20000g) and frozen for subsequent prothrombin time and drug leveldeterminations.

[0257] The plasma concentration of the compound is extrapolated from thestandard curve and expressed in Anti-Factor Xa units. Thrombus weight ismeasured following dosing of vehicle or test compound. Data is expressedas % inhibition of thrombus formation in the presence of compound whencompared to thrombus weight from a group of control animals.

[0258] Although the pharmacological potencies of the compounds offormula I vary with structural changes as expected, in general compoundsof the formula I possess activity at the following concentrations ordoses in at least one of the above tests a) to c):—

[0259] test a): IC₅₀ (Factor Xa) in the range, for example, 0.001-25 μM;

[0260] test b): IC₅₀ (thrombin), for example, greater than 40 μM;

[0261] test c): CT2 (PT) in the range, for example, 0.1-50 μM.

[0262] By way of example, the compound of Example 1 as disclosedhereinafter has an IC₅₀ of 0.013 μM against Factor Xa in test a), anIC₅₀, of greater than 40 μM against thrombin in test b) and a CT2 (PT)of 5 μM in test c).

[0263] According to a further feature of the invention there is provideda pharmaceutical composition which comprises an aminoheterocyclicderivative of the formula I, or a pharmaceutically-acceptable saltthereof, in association with a pharmaceutically-acceptable diluent orcarrier.

[0264] The composition may be in a form suitable for oral use, forexample a tablet, capsule, aqueous or oily solution, suspension oremulsion; for topical use, for example a cream, ointment, gel or aqueousor oily solution or suspension; for nasal use, for example a snuff,nasal spray or nasal drops; for vaginal or rectal use, for example asuppository; for administration by inhalation, for example as a finelydivided powder such as a dry powder, a microcrystalline form or a liquidaerosol; for sub-lingual or buccal use, for example a tablet or capsule;or for parenteral use (including intravenous, subcutaneous,intramuscular, intravascular or infusion), for example a sterile aqueousor oily solution or suspension. In general the above compositions may beprepared in a conventional manner using conventional excipients.

[0265] The amount of active ingredient (that is an aminoheterocyclicderivative of the formula I, or a pharmaceutically-acceptable saltthereof) that is combined with one or more excipients to produce asingle dosage form will necessarily vary depending upon the host treatedand the particular route of administration. For example, a formulationintended for oral administration to humans will generally contain, forexample, from 0.5 mg to 2 g of active agent compounded with anappropriate and convenient amount of excipients which may vary fromabout 5 to about 98 percent by weight of the total composition. Dosageunit forms will generally contain about 1 mg to about 500 mg of anactive ingredient.

[0266] According to a further feature of the invention there is providedan aminoheterocyclic derivative of the formula I, or apharmaceutically-acceptable salt thereof, for use in a method oftreatment of the human or animal body by therapy.

[0267] The invention also includes the use of such an active ingredientin the production of a medicament for use in:—

[0268] (i) producing a Factor Xa inhibitory effect;

[0269] (ii) producing an anticoagulant effect;

[0270] (iii) producing an antithrombotic effect;

[0271] (iv) treating a Factor Xa mediated disease or medical condition;

[0272] (v) treating a thrombosis mediated disease or medical condition;

[0273] (vi) treating coagulation disorders; and/or

[0274] (vii) treating thrombosis or embolism involving Factor Xamediated coagulation.

[0275] The invention also includes a method of producing an effect asdefined hereinbefore or treating a disease or disorder as definedhereinbefore which comprises administering to a warm-blooded animalrequiring such treatment an effective amount of an active ingredient asdefined hereinbefore.

[0276] The size of the dose for therapeutic or prophylactic purposes ofa compound of the formula I will naturally vary according to the natureand severity of the medical condition, the age and sex of the animal orpatient being treated and the route of administration, according to wellknown principles of medicine. As mentioned above, compounds of theformula I are useful in the treatment or prevention of a variety ofmedical disorders where anticoagulant therapy is indicated. In using acompound of the formula I for such a purpose, it will generally beadministered so that a daily dose in the range, for example, 0.5 to 500mg/kg body weight is received, given if required in divided doses. Ingeneral lower doses will be administered when a parenteral route isemployed, for example a dose for intravenous administration in therange, for example, 0.5 to 50 mg/kg body weight will generally be used.For preferred and especially preferred compounds of the invention, ingeneral, lower doses will be employed, for example a daily dose in therange, for example, 0.5 to 10 mg/kg body weight.

[0277] Although the compounds of the formula I are primarily of value astherapeutic or prophylactic agents for use in warm-blooded animalsincluding man, they are also useful whenever it is required to producean anticoagulant effect, for example during the ex-vivo storage of wholeblood or in the development of biological tests for compounds havinganticoagulant properties.

[0278] The compounds of the invention may be administered as a soletherapy or they may be administered in conjunction with otherpharmacologically active agents such as a thrombolytic agent, forexample tissue plasminogen activator or derivatives thereof orstreptokinase. The compounds of the invention may also be administeredwith, for example, a known platelet aggregation inhibitor (for exampleaspirin, a thromboxane antagonist or a thromboxane synthase inhibitor),a known hypolipidaemic agent or a known anti-hypertensive agent.

[0279] The invention will now be illustrated in the following Examplesin which, unless otherwise stated:—

[0280] (i) evaporations were carried out by rotary evaporation in vacuoand work-up procedures were carried out after removal of residual solidsby filtration;

[0281] (ii) operations were carried out at room temperature, that is inthe range 18-25° C. and under an atmosphere of an inert gas such asargon;

[0282] (iii) column chromatography (by the flash procedure) and mediumpressure liquid chromatography (MPLC) were generally performed on MerckKieselgel silica (Art. 9385) or Merck Lichroprep RP-18 (Art. 9303)reversed-phase silica obtained from E. Merck, Darmstadt, Germany;alternatively high pressure liquid chromatography (HPLC) was performedon a Dynamax C-18 60 Å preparative reversed-phase column;

[0283] (iv) yields are given for illustration only and are notnecessarily the maximum attainable;

[0284] (v) the end-products of the formula I have satisfactorymicroanalyses and their structures were confirmed by nuclear magneticresonance (NMR) at 200, 250 or 300 MHz and mass spectral techniques;unless otherwise stated, CD₃SOCD₃ solutions of the end-products of theformula I were used for the determination of NMR spectral data, chemicalshift values were measured on the delta scale; the followingabbreviations have been used: s, singlet; d, doublet; t, triplet; q,quartet; m, multiplet;

[0285] (vi) intermediates were not generally fully characterised andpurity was assessed by thin layer chromatographic, infra-red (IR) or NMRanalysis;

[0286] (vii) melting points were determined using a Mettler SP62automatic melting point apparatus or an oil-bath apparatus; meltingpoints for the end-products of the formula I were generally determinedafter crystallisation from a conventional organic solvent such asethanol, methanol, acetone, ether or hexane, alone or in admixture; and

[0287] (viii) the following abbreviations have been used:— DMFN,N-dimethylformamide; THF tetrahydrofuran; DMSO dimethylsulphoxide.EDAC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride BOCtert-butyloxycarbonyl

EXAMPLE 1

[0288] 1,1′-Carbonyldiimidazole (0.15 g) was added to a stirred solutionof 4-(6-chloronaphth-2-ylsulphonyl)benzoic acid (0.29 g) in DMF (10 ml)which had been cooled to 0° C. and the mixture was stirred at 0° C. for30 minutes. N-(4-Pyridyl)piperazine (0.164 g) was added, the coolingbath was removed and the mixture was stirred at ambient temperature for16 hours. The solvent was removed by evaporation and the residue waspartitioned between ethyl acetate and water. The ethyl acetate extractwas washed with water and with brine, dried (MgSO4) and evaporated. Theresidue was triturated under diethyl ether to give1-[4-(6-chloronaphth-2-ylsulphonyl)benzoyl]-4-(4-pyridyl)piperazine(0.085 g), m.p. 267-269° C.;

[0289] NMR Spectrum 3.25-3.5 (m, 6H), 3.6-3.9 (m, 2H), 6.75 (d, 2H),7.65 (d, 2H), 7.77 (m, 1H), 8.0 (m, 1H), 8.05-8.25 (m, 6H), 8.3 (d, 1H),8.6 (s, 1H);

[0290] Mass Spectrum m/z 492 (M+H);

[0291] Elemental Analysis Found C, 63.1; H, 4.7; N, 8.2; C26H22ClN3O3S2H2O requires C, 63.5; H, 4.5; N, 8.5%.

[0292] The 4-(6-chloronaphth-2-ylsulphonyl)benzoic acid used as astarting material was prepared as follows:—

[0293] A solution of sodium nitrite (2.7 g) in water (5 ml) was addedduring 2 hours to a stirred mixture of 6-amino-2-naphthalenesulphonicacid (8.8 g), dilute aqueous hydrochloric acid (2.8% weight/volume, 20ml) and water (15 ml) which had been cooled to 0° C. The mixture wasstirred at 0° C. for 30 minutes and then poured onto a stirredsuspension of cuprous chloride (3.96 g) in dilute aqueous hydrochloricacid (2.8%, 20 ml). The mixture was evaporated to give6-chloro-2-naphthalenesulphonic acid which was used without furtherpurification.

[0294] The material was suspended in DMF (40 ml) and cooled to 5° C.Thionyl chloride (8.6 ml) was added dropwise and the mixture was stirredat 5° C. for 3 hours. The mixture was poured onto ice and extracted withmethylene chloride. The organic solution was dried (MgSO4) andevaporated. The residue was purified by column chromatography using a20:1 mixture of hexane and ethyl acetate as eluent. There was thusobtained 6-chloronaphth-2-ylsulphonyl chloride (2.49 g);

[0295] NMR Spectrum 7.45 (m, 1H), 7.8 (m, 1H), 7.85 (d, 1H), 8.05 (m,2H), 8.2 (s, 1H).

[0296] 6-Chloronaphth-2-ylsulphonyl chloride (2.61 g) was added in oneportion to a stirred mixture of sodium sulphite heptahydrate (4.71 g),sodium bicarbonate (1.64 g) and water (25 ml) which had been heated to70° C. The resultant mixture was heated to that temperature for 3 hoursand then allowed to cool slowly to ambient temperature. The crystallineprecipitate was isolated giving sodium 6-chloronaphth-2-ylsulphinate(2.4 g) which was used without further purification.

[0297] A mixture of a portion (0.5 g) of the material so obtained,4-fluorobenzaldehyde (0.25 g) and DMSO (10 ml) was stirred and heated to110° C. for 5 hours. A second portion (0.5 g) of the sodium6-chloronaphth-2-ylsulphinate was added and the mixture was heated to110° C. for a further 10 hours. The mixture was cooled to ambienttemperature and partitioned between ethyl acetate and water. The organicextract was washed with water and with brine, dried (MgSO4) andevaporated. The residue was purified by column chromatography using a1:1 mixture of hexane and ethyl acetate as eluent. There was thusobtained 4-(6-chloronaphth-2-ylsulphonyl)benzaldehyde (0.25 g);

[0298] NMR Spectrum 7.7 (m, 1H), 8.0 (m, 1H), 8.1-8.3 (m, 7H), 8.8 (s,1H), 10.0 (s, 1H).

[0299] After repetition of the previous steps, potassium permanganate(0.4 g) was added in small portions during 1 hour to a stirred mixtureof 4-(6-chloronaphth-2-ylsulphonyl)-benzaldehyde (0.58 g),cetyltrimethylammonium bromide (0.056 g) and water (25 ml) which hadbeen heated to 60° C. The mixture was heated to 60° C. for a further 2hours. The mixture was cooled to ambient temperature and acidified bythe addition of 2M aqueous hydrochloric acid. Ethyl acetate was added.The mixture was filtered through a pad of diatomaceous earth. The solidwas washed thoroughly in turn with methylene chloride and with ethylacetate. The organic solutions were combined, dried (MgSO4), andevaporated. The residue was purified by column chromatography usingincreasingly polar mixtures of methylene chloride and methanol aseluent. There was thus obtained 4-(6-chloronaphth-2-ylsulphonyl)benzoicacid (0.376 g);

[0300] NMR Spectrum 7.7 (m, 1H); 7.95 (m, 1H); 8.1-8.2 (m, 6H); 8.6 (s,1H).

EXAMPLE 2

[0301] Using an analogous procedure to that described in Example 1,N-(4-pyridyl)piperazine was reacted with 4-(2-naphthylsulphonyl)benzoicacid to give 1-[4-(2-naphthylsulphonyl)-benzoyl]-4-(4-pyridyl)piperazinein 32% yield;

[0302] NMR Spectrum 3.25-3.5 (m, 6H), 3.6-3.9 (m, 2H), 6.8 (d, 2H), 7.7(d, 2H), 7.77 (m, 1H), 7.95 (m, 1H), 8.05-8.25 (m, 8H), 8.77 (d, 1H);

[0303] Mass Spectrum m/z 457 (M+H);

[0304] Elemental Analysis Found C, 63.5: H, 5.5: N, 8.6; C26H23N3O3S2H2O requires C, 63.5: H, 5.5: N, 8.6%.

[0305] The 4-(2-naphthylsulphonyl)benzoic acid used as a startingmaterial was prepared from 4-fluorobenzaldehyde and sodium2-naphthylsulphinate using analogous procedures to those described inthe fourth and fifth paragraphs of the portion of Example 1 which isconcerned with the preparation of starting materials. There was thusobtained 4-(2-naphthylsulphonyl)benzoic acid in 28% yield;

[0306] NMR Spectrum 7.7 (m, 1H), 7.95 (m, 1H), 8.1-8.2 (m, 8H), 8.7 (d,1H).

EXAMPLE 3

[0307] Glacial acetic acid (0.178 g) was added to a mixture ofN-(4-pyridyl)piperazine (0.121 g),4-(6-bromonaphth-2-ylsulphonyl)benzaldehyde (0.278 g) and methylenechloride (10 ml) and the mixture was stirred at ambient temperature for30 minutes. Sodium triacetoxyborohydride (0.236 g) was added and themixture was stirred at ambient temperature for 16 hours. Water (50 ml)was added and the mixture was acidified by the addition of 2M aqueoushydrochloric acid. The resultant mixture was washed with diethyl ether.The aqueous phase was basified by the addition of 2M aqueous sodiumhydroxide solution and extracted with methylene chloride. The resultantorganic phase was dried (MgSO4), and evaporated. The residue waspurified by column chromatography using increasingly polar, mixtures ofmethylene chloride and methanol as eluent. There was thus obtained1-[4-(6-bromonaphth-2-ylsulphonyl)benzyl]4-(4-pyridyl)piperazine (0.127g) as a gum;

[0308] NMR Spectrum 3.2-3.4 (m, 8H), 3.6 (s, 2H), 6.75 (d, 2H), 7.6 (d,2H), 7.75 (m, 1H), 7.95 (m, 3H), 8.1-8.2 (m, 4H), 8.3 (d, 1H), 8.75 (s,1H);

[0309] Mass Spectrum m/z 522 (M+H);

[0310] Elemental Analysis Found C, 58.6: H, 4.5: N, 7.8; C26H24BrN3O2S0.15CH2Cl2 requires C, 58.7: H, 4.6: N, 7.9%.

[0311] The 4-(6-bromonaphth-2-ylsulphonyl)benzaldehyde used as astarting material was obtained as follows:—

[0312] 6-Bromonaphth-2-ylsulphonyl chloride was obtained in 22% yieldfrom 6-amino-2-naphthalenesulphonic acid using an analogous procedure tothat described in the first two paragraphs of the portion of Example 1which is concerned with the preparation of starting materials exceptthat hydrobromic acid and cuprous bromide were used in place ofhydrochloric acid and cuprous chloride respectively. The material gavethe following NMR signals: 7.65 (m, 1H), 7.75-8.0 (m, 3H), 8.15-8.2 (m,2H).

[0313] 6-Bromonaphth-2-ylsulphonyl chloride (9.4 g) was added in smallportions over 3 hours to a stirred mixture of sodium sulphiteheptahydrate (14.46 g), sodium bicarbonate (5.08 g) and water (100 ml)which had been heated to 70° C. The resultant mixture was allowed tocool slowly to ambient temperature. The crystalline precipitate wasisolated giving sodium 6-bromonaphth-2-ylsulphinate (8.07 g) which wasused without further purification.

[0314] A mixture of a portion (1.47 g) of the material so obtained,4-fluorobenzaldehyde (0.72 g) and DMSO (20 ml) was stirred and heated to110° C. for 4 hours and at 80° C. for 12 hours. The mixture was cooledto ambient temperature and partitioned between ethyl acetate and water.The organic extract was washed with water and with brine, dried (MgSO4)and evaporated. The residue was purified by column chromatography usingincreasingly polar mixtures of hexane and ethyl acetate as eluent. Therewas thus obtained 4-(6-bromonaphth-2-ylsulphonyl)benzaldehyde (0.28 g);

[0315] NMR Spectrum 7.8 (m, 1H), 8.0 (m, 1H), 8.1-8.2 (m, 6H), 8.4 (d,1H), 8.8 (s, 1H), 10.1 (s, 1H).

EXAMPLE 4

[0316] A solution of 4′-bromo-4-biphenylylsulphonyl chloride (0.33 g) inmethylene chloride (5 ml) was added dropwise to a stirred solution of4-[1-(4-pyridyl)piperidin-4-yloxy]aniline (0.269 g) in methylenechloride (20 ml) and the mixture was stirred at ambient temperature for16 hours. The precipitated solid was collected by filtration andtriturated under methanol (5 ml). The resultant solid was washed withdiethyl ether. There was thus obtained4′-bromo-N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-4-biphenylylsulphonamide,hydrochloride salt, (0.508 g), m.p. 302-304° C.;

[0317] NMR Spectrum 1.66 (m, 2H), 1.99 (m, 2H), 3.58 (m, 2H), 3.86 (m,2H), 4.60 (m, 1H), 6.89 (d, 2H), 7.03 (d, 2H), 7.18 (d, 2H) 7.67 (s,4H), 7.76 (d, 2H), 7.84 (d, 2H), 8.19 (d, 2H), 10.05 (s, 1H);

[0318] Mass Spectrum m/z 564/566 (M+H);

[0319] Elemental Analysis Found C, 54.6; H, 4.7; N, 6.9; S, 5.2;C₂₈H₂₆BrN₃O₃S 1HCl 1H₂O requires C, 54.3; H, 4.7; N, 6.8; S, 5.2%.

[0320] The 4-[1-(4-pyridyl)piperidin-4-yloxy]aniline used as startingmaterial was obtained as follows:—

[0321] 1,1′-(Azodicarbonyl)dipiperidine (20.03 g), tributylphosphine(16.06 g) and 1-(4-pyridyl)piperidin-4-ol (Chemical Abstracts, vol. 113,abstract 23121 In; European Patent Application No. 0 359 389; 9.43 g)were added in turn to a stirred solution of4-(N-tert-butoxycarbonylamino)phenol (J. Med. Chem., 1995, 38, 3983;11.08 g) in THF (300 ml) which was cooled to 10° C. The mixture wasstirred at ambient temperature for 20 hours. The precipitate was removedby filtration and the filtrate was evaporated. The residue was purifiedby column chromatography using initially ethyl acetate and thenincreasingly polar mixtures of methylene chloride and methanol aseluent. There was thus obtained tert-butylN-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}carbamate (7.38 g), m.p.192-195° C., which was used without further purification.

[0322] A solution of a portion (4.22 g) of the material so obtained inmethylene chloride (400 ml) was treated with a saturated solution ofhydrogen chloride in diethyl ether (50 ml). The mixture was stirred atambient temperature for 64 hours. The mixture was evaporated and theresidue was crystallised under a mixture of diethyl ether and methanolto give the hydrochloride salt of the required starting material (2.85g), m.p. 289-291° C. A portion (1.5 g) of the material was dissolved inwater (10 ml) and a 2M aqueous sodium hydroxide solution was added untilprecipitation was complete. There was thus obtained4-[1-(4-pyridyl)piperidin-4-yloxy]aniline (1.03 g), m.p. 214-215° C.;

[0323] NMR Spectrum 1.57 (m, 2H), 1.86 (m, 2H), 3.24 (m, 2H), 3.67 (m,2H), 4.31 (m, 1H), 6.47 (d, 2H), 6.66 (d, 2H), 6.87 (d, 2H), 8.13 (d,2H).

[0324] The 4′-bromo-4-biphenylylsulphonyl chloride used as a startingmaterial was obtained as follows:—

[0325] Chlorosulphonic acid (8.3 ml) was added dropwise to a stirredsolution of 4-bromobiphenyl (23.3 g) in chloroform (200 ml) and themixture was stirred at ambient temperature for 30 minutes. Theprecipitate was isolated and washed with chloroform. There was thusobtained 4′-bromo-4-biphenylylsulphonic acid (30.3 g).

[0326] Thionyl chloride (21.2 ml) was added dropwise to a stirredsolution of 4′-bromo-4-biphenylylsulphonic acid (30.3 g) in DMF (120 ml)which had been cooled to 5° C. The mixture was stirred at ambienttemperature for 3 hours. The mixture was poured into a mixture of iceand water (1L) and the resultant precipitate was isolated, dissolved indiethyl ether, dried (MgSO4) and re-isolated by evaporation of thesolvent. There was thus obtained 4′-bromo-4-biphenylyl-sulphonylchloride (24.1 g) [after crystallisation of the residue from a 1:1mixture of isohexane and toluene], m.p. 125-127° C.

EXAMPLE 5

[0327] Using an analogous procedure to that described in Example 4,4-[1-(4-pyridyl)-piperidin-4-yloxy]aniline was reacted with(E)-4-chlorostyrylsulphonyl chloride. The reaction product was purifiedby column chromatography on a C-18 60 Å preparative reversed-phase HPLCcolumn using 0.1% trifluoroacetic acid in aqueous acetonitrile and agradient of 30% to 70% acetonitrile as eluent. There was thus obtained4-chloro-N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-(E)-styrylsulphonamide,trifluoroacetate salt, as a gum in 10% yield;

[0328] NMR Spectrum 1.64 (m, 2H), 1.99 (m, 2H), 3.62 (m, 2H), 3.91 (m,2H), 4.64 (m, 1H), 6.82-7.42 (m, 8H), 7.46 (d, 2H), 7.72 (d, 2H), 8.23(d, 2H), 9.75 (s, 1H);

[0329] Mass Spectrum m/z 470/472 (M+H).

[0330] The (E)-4-chlorostyrylsulphonyl chloride used as a startingmaterial was obtained as follows:—

[0331] Sulphuryl chloride (1.37 ml) was added dropwise to DMF (1.55 ml)which was stirred and cooled to a temperature in the range 0 to 5° C.The mixture was then stirred at ambient temperature for 30 minutes.4-Chlorostyrene (1.2 ml) was added and the mixture was stirred andheated to 90° C. for 3.5 hours. The mixture was cooled to ambienttemperature and poured onto a mixture (25 ml) of ice and water. Theprecipitate was isolated, washed with water and dried. There was thusobtained (E)-4-chloro-p-styrylsulphonyl chloride (1.8 g);

[0332] NMR Spectrum 6.95 (s, 2H), 7.4 (d, 2H), 7.55 (d, 2H).

EXAMPLE 6

[0333] 6-Bromonaphth-2-ylsulphonyl chloride (0.1 g) was added to amixture of 4-[1-(4-pyridyl)piperidin-4-yloxy]aniline (0.1 g),triethylamine (0.168 g) and methylene chloride (5 ml) and the mixturewas stirred at ambient temperature for 16 hours. The mixture wasevaporated and the residue was purified on a C-18 60 Å preparativereversed-phase HPLC column using 0.1% trifluoroacetic acid in aqueousacetonitrile and a gradient of 60% to 95% acetonitrile as eluent. Therewere thus obtained inturn:—6-bromo-N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-2-naphthalenesulphonamide,trifluoroacetate salt, as a gum (0.026 g);

[0334] NMR Spectrum 1.64 (m, 2H), 1.97 (m, 2H), 3.57 (m, 2H), 3.87 (m,2H), 4.58 (m, 1H), 6.83 (d, 2H) 6.99 (d, 2H), 7.19 (d, 2H), 7.75 (q,1H), 7.80 (q, 1H), 8.07 (d, 2H), 8.20 (d, 2H), 8.33 (d, 2H), 10.07 (s,1H), 13.27 (broad s, 1H);

[0335] Mass Spectrum m/z 538/540 (M+H);

[0336] and6-bromo-N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-N-(6-bromonaphth-2-ylsulphonyl)-2-naphthalenesulphonamide,trifluoroacetate salt, as a waxy solid (0.031 g), m.p. 130-135° C.;

[0337] NMR Spectrum 1.67 (m, 2H), 2.07 (m, 2H), 3.62 (m, 2H), 3.94 (m,2H), 4.76 (m, 1H), 6.99 (m, 4H), 7.22 (d, 2H), 7.86 (m, 41), 8.06-8.27(m, 6H), 8.45 (d, 4H);

[0338] Mass Spectrum m/z 808 (M+H).

EXAMPLE 7

[0339] Using an analogous procedure to that described in Example 4,4-[1-(4-pyridyl)piperidin-4-yloxy]aniline was reacted with4-toluenesulphonyl chloride to giveN-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-4-toluenesulphonamide,hydrochloride salt, in 54% yield, m.p. 270-272° C.;

[0340] NMR Spectrum 1.63 (m, 2H), 1.97 (m, 2H), 2.31 (s, 3H), 3.57 (m,2H), 3.88 (m, 2H), 4.60 (m, 1H), 6.84 (d, 2H), 6.98 (d, 2H), 7.20 (d,2H), 7.31 (d, 2H), 7.57 (d, 2H), 8.19 (d, 2H), 9.88 (s, 1H);

[0341] Mass Spectrum i/z 424 (M+H);

[0342] Elemental Analysis Found C, 57.7; H, 5.5; N, 8.7; C₂₃H₂₅N₃O₃S1HCl 1H₂O requires; C, 57.8; H, 5.9; N, 8.8%.

EXAMPLE 8

[0343] Using an analogous procedure to that described in Example 6,N-{4-[1*4-pyridyl)-piperidin-4-yloxy]phenyl}4-toluenesulphonamide,hydrochloride salt, was reacted with 4-toluenesulphonyl chloride. Thecrude reaction product was triturated under water. There was thusobtainedN-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-N-(4-tolylsulphonyl)-4-toluenesulphonamidein 85% yield, m.p. 196-198° C.;

[0344] NMR Spectrum 1.65 (m, 2H), 2.02 (m, 2H), 2.46 (s, 6H), 3.20 (m,2H), 3.72 (m, 2H), 4.68 (m, 1H), 6.84 (m, 4H), 7.02 (d, 2H), 7.48 (d,4H), 7.68 (d, 4H), 8.16 (d, 2H);

[0345] Mass Spectrum n/z 578 (M+H).

EXAMPLE 9

[0346] Sodium hydride (60% dispersion in mineral oil, 0.06 g) was addedto a stirred mixture of4′-bromo-N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-4-biphenylylsulphonamide,hydrochloride salt (0.309 g), THF (10 ml) and DMF (1 ml), and themixture was stirred at ambient temperature for 45 minutes. Methyl iodide(0.142 g) was added and stirring was continued for 16 hours. The mixturewas evaporated. The residue was triturated under water and the resultantsolid was purified by column chromatography using increasingly polarmixtures of methylene chloride and methanol as eluent. There was thusobtained4′-bromo-N-methyl-N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-4-biphenylylsulphonamide,as a foam (0.045 g);

[0347] NMR Spectrum (CDCl₃) 2.00 (m, 4H), 3.20 (s, 3H), 3.41 (m, 2H),3.65 (m, 2H), 4.57 (m, 1H), 6.74 (d, 2H), 6.84 (d, 2H), 7.05 (d, 2H),7.47 (d, 2H), 7.61 (m, 6H), 8.25 (d, 2H);

[0348] Mass Spectrum m/z 578/580 (M+H).

EXAMPLE 10

[0349] Using an analogous procedure to that described in Example 4,N-methyl-4-[1-(4-pyridyl)piperidin-4-yloxy]aniline was reacted with(E)-4-chlorostyrylsulphonyl chloride. The yellow reaction liquor wasdecanted from a brown gum (which was discarded) and evaporated. Theresultant foam was purified by column chromatography on alumina (ICNalumina N, grade 3) using methylene chloride as eluent. There was thusobtained4-chloro-N-methyl-N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-(E)-styrylsulphonamide,as a gum in 34% yield;

[0350] NMR Spectrum 1.63 (m, 2H), 1.97 (m, 2H), 2.25 (m, 2H), 3.19 (s,3H), 3.68 (m, 2H), 4.62 (m, 1H), 6.80 (d, 2H), 6.96 (d, 2H), 7.25 (d,2H) 7.26 (d, 1H), 7.36 (d, 1H), 7.47 (d, 2H), 7.76 (d, 2H), 8.12 (d,2H);

[0351] Mass Spectrum m/z 484/486 (M+H).

[0352] The N-methyl-4-[1-(4-pyridyl)piperidin-4-yloxy]aniline used as astarting material was prepared as follows:—

[0353] Acetic formic anhydride (1.5 g; pre-formed by heating aceticanhydride and 98% formic acid at 60° C. for 2 hours) was cooled to 5° C.and 4-[1-(4-pyridyl)piperidin-4-yloxy]aniline (1.0 g) was added. Themixture was stirred at ambient temperature for 16 hours and thenevaporated. The residue was dissolved in water (50 ml) and the mixturewas basified to pH 110 by the addition of a 2M aqueous sodium hydroxidesolution. The resultant mixture was extracted with methylene chloride,washed with water and with brine, dried (MgSO4) and evaporated to giveN-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}formamide as a foam (0.72g);

[0354] NMR Spectrum 1.63 (m, 2H), 1.96 (m, 2H), 3.22 (m, 2H), 3.67 (m,2H), 4.56 (m, 1H), 6.82 (d, 2H), 6.94 (d, 2H), 7.48 (d, 2H), 8.12 (d,2H), 8.20 (d, 1H), 9.96 (broad s, 1H);

[0355] Mass Spectrum m/z 298 (M+H).

[0356] The material so formed was dissolved in THF (5 ml) and added to astirred suspension of lithium aluminium hydride (0.18 g) in THF (5 ml).The mixture was stirred at ambient temperature for 16 hours. The minimumvolume of a saturated aqueous ammonium chloride solution was added todestroy the excess of reducing agent. THF (50 ml) was added, the mixturewas filtered and the filtrate was evaporated to giveN-methyl-4-[1-(4-pyridyl)piperidin-4-yloxy]aniline as a pale yellowsolid (0.62 g), m.p. 161-164° C.;

[0357] NMR Spectrum (CDCl₃) 1.82 (m, 2H), 1.98 (m, 2H), 2.82 (s, 3H),3.27.(m, 2H), 3.64 (m, 2H), 4.34 (m, 1H), 6.57 (d, 2H), 6.66 (d, 2H),6.82 (d, 2H), 8.25 (d, 2H);

[0358] Mass Spectrum m/z 284 (M+H).

EXAMPLE 11

[0359] Using an analogous procedure to that described in Example 4,4-[1-(4-pyridyl)piperidin-4-ylmethoxy]aniline was reacted with4′-bromo-4-biphenylylsulphonyl chloride. The crude reaction product waswashed with methylene chloride. There was thus obtained4′-bromo-N-{4-[1-(4-pyridyl)piperidin-4-ylmethoxy]phenyl}4-biphenylylsulphonamide,hydrochloride salt, as a white solid in 77% yield, m.p. 293-295° C.;

[0360] NMR Spectrum 1.30 (q, 2H), 1.87 (d, 2H), 2.21 (m, 1H). 3.18 (m,2H), 3.78 (d, 2H), 4.22 (d, 2H), 6.81 (d, 2H), 7.01 (d, 2H), 7.18 (d,2H) 7.67 (s, 4H), 7.77 (d. 2H), 7.84 (d, 2H), 8.18 (d, 2H), 10.0 (s,1H), 13.3 (broad s, 1H);

[0361] Mass Spectrum m/z 578/580 (M+H);

[0362] Elemental Analysis Found C, 55.8; H, 4.9; N, 6.6; C₂₉H₂₈BrN₃O₃S1HCl 1.5H₂O requires C, 55.8; H, 4.9; N, 6.7%.

[0363] The 4-[1-(4-pyridyl)piperidin-4-ylmethoxy]aniline used asstarting material was obtained as follows:—

[0364] Using an analogous procedure to that used in the first paragraphof the portion of Example 4 which is concerned with the preparation ofstarting materials, 1-(4-pyridyl)-piperidin-4-ylmethanol (ChemicalAbstracts, vol. 113, abstract 23121 In; European Patent Application No.0 359 389) was reacted with 4-(N-tert-butoxycarbonylamino)phenol. Theresultant product was treated with a saturated solution of hydrogenchloride in diethyl ether using an analogous procedure to that used inthe second paragraph of the portion of Example 4 which is concerned withthe preparation of starting materials. There was thus obtained4-[1-(4-pyridyl)piperidin-4-ylmethoxy]aniline in 22% yield, m.p.210-211° C.

EXAMPLE 12

[0365] Using an analogous procedure to that described in Example 4,4-[1-(4-pyridyl)piperidin-4-ylmethoxy]aniline was reacted with6-bromonaphth-2-ylsulphonyl chloride. There was thus obtained6-bromo-N-{4-[1-(4-pyridyl)piperidin-4-ylmethoxy]-phenyl}-2-naphthalenesulphonamide,hydrochloride salt, as a white solid in 76% yield, m.p. 167-169° C.;

[0366] NMR Spectrum 1.26 (m, 2H), 1.84 (d, 2H), 2.10 (m, 1H), 3.15 (m,2H), 3.72 (d, 2H), 4.20 (d, 2H), 6.75 (d, 2H), 6.96 (d, 2H), 7.16 (d,2H), 7.76 (m, 2H), 8.05 (d, 2H), 8.16 (d, 2H), 8.31 (d, 2H), 10.05 (s,1H);

[0367] Mass Spectrum m/z 552/554 (M+H);

[0368] Elemental Analysis Found C, 53.7; H, 4.9; N, 7.1; C₂₇H₂₆BrN₃O₃S1HCl 1H₂O requires C, 53.3; H, 5.0; N, 6.9%.

EXAMPLE 13

[0369] Using an analogous procedure to that described in Example 4,4-[1-(4-pyridyl)piperidin-4-ylmethoxy]aniline was reacted with(E)-4-chlorostyrylsulphonyl chloride. There was thus obtained4-chloro-N-{4-[1-(4-pyridyl)piperidin-4-ylmethoxy]phenyl}-(E)-styrylsulphonamide,hydrochloride salt, in 34% yield, m.p. 220-223° C.;

[0370] NMR Spectrum 1.30 (m, 2H), 1.88 (d, 2H), 2.13 (m, 1H), 3.14 (m,2H), 3.79 (d, 2H), 4.22 (d, 2H), 6.84 (d, 2H), 7.10 (d, 2H), 7.15 (d,2H), 7.17 (d, 1H), 7.32 (d, 1H), 7.43 (d, 2H), 7.68 (d, 2H), 8.17 (d,2H), 9.69 (s, 1H);

[0371] Mass Spectrum m/z 484/486 (M+H);

[0372] Elemental Analysis Found C, 54.7; H, 5.2; N, 7.7; C₂₅H₂₆ClN₃O₃S1HCl 1.5H₂O requires C, 54.9; H, 5.5; N, 7.7%.

EXAMPLE 14

[0373] Using an analogous procedure to that described in Example 6.4′-bromo-N-{4-[1-(4-pyridyl)piperidin-4-ylmethoxy]phenyl}-4-biphenylylsulphonamide,hydrochloride salt, was reacted with 4′-bromo-4-biphenylylsulphonylchloride. There was thus obtained4′-bromo-N-(4′-bromo-4-biphenylylsulphonyl)-N-{4-[1-(4-pyridyl)piperidin-4-ylmethoxy]phenyl}-4-biphenylylsulphonamidein 91% yield, m.p. 136-140° C.;

[0374] NMR Spectrum 1.31 (m, 2H), 1.84 (d, 2H), 2.05 (m, 1H), 2.89 (t,2H). 3.88 (d, 2H), 3.98 (d, 2H), 6.83 (d, 2H), 6.99 (s, 4H), 7.73 (s,8H), 7.89 (d, 4H), 7.99 (d, 4H), 8.12 (d, 2H);

[0375] Mass Spectrum m/z 874 (M+H).

EXAMPLE 15

[0376] Using an analogous procedure to that described in Example 6,6-bromo-N-{4-[1-(4-pyridyl)piperidin-4-ylmethoxy]phenyl}-2-naphthalenesulphonamide,hydrochloride salt, was reacted with 6-bromonaphth-2-ylsulphonylchloride. There was thus obtained6-bromo-N-(6-bromonaphth-2-ylsulphdnyl)-N-{4-[1-(4-pyridyl)piperidin-4-ylmethoxy]phenyl}-2-naphthalenesulphonamidein 99% yield, m.p. 246-252° C.;

[0377] NMR Spectrum 1.47 (m, 2H), 1.93 (d, 2H), 2.07 (m, 0.1H), 2.91 (t,2H), 3.82 (d, 2H), 3.94 (d, 2H), 6.67 (d, 2H), 6.81 (d, 2H), 6.94 (d,2H), 7.71 (d, 2H), 7.82 (d, 2H), 7.90 (d, 2H), 7.99 (d, 2H), 8.13 (s,2H), 8.26 (d, 2H), 8.43 (s, 2H);

[0378] Mass Spectrum m/z 822 (M+H).

EXAMPLE 16

[0379] Using an analogous procedure to that described in Example 4except that the reaction mixture was stirred at ambient temperature for71 hours, 3-[1-(4-pyridyl)piperidin-4-yloxy]aniline was reacted with6-bromonaphth-2-ylsulphonyl chloride. The product was washed withmethylene chloride and dried. There was thus obtained6-bromo-N-{3-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-2-naphthalenesulphonamide,hydrochloride salt, in 77% yield, m.p. 298-300° C.;

[0380] NMR Spectrum 1.63 (m, 2H), 1.92 (m, 2H), 3.57 (m, 2H), 3.81 (m,2H), 4.57 (m, 1H), 6.70 (m, 3H), 7.18 (m, 3H), 7.77 (m, 2H), 8.08 (m,2H), 8.21 (d, 2H), 8.30 (s, 1H), 8.47 (s, 1H), 10.41 (s, 1H), 13.47(broads, 1H);

[0381] Mass Spectrum m/z 538/540 (M+H);

[0382] Elemental Analysis Found C, 53.8; H, 4.5; N, 7.2; C₂₆H₂₄N₃O₃S1HCl 0.25H₂O requires: C, 53.9; H, 4.4; N, 7.25%.

[0383] The 3-[1-(4-pyridyl)piperidin-4-yloxy]aniline used as a startingmaterial was prepared as follows:—

[0384] Diethyl azodicarboxylate (3 ml) was added over 15 minutes to astirred mixture of 1-(4-pyridyl)piperidin-4-ol (3.39 g),3-(N-tert-butoxycarbonylamino)phenol (Chemical Abstracts, vol. 119,abstract 139113; PCT Patent Application WO 9306085; 3.98 g),triphenylphosphine (4.99 g) and THF (150 ml) which had been cooled to 4°C. The resultant mixture was stirred for 48 hours at ambienttemperature. The solvent was evaporated and the residue was purified bycolumn chromatography using a 9:1 mixture of methylene chloride andmethanol as eluent. The resultant foam was crystallised from diethylether to give tert-butylN-{3-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}carbamate (4.65 g), m.p.165-166° C.

[0385] A 2.2M solution of hydrogen chloride in methanol (45 ml) wasadded over 15 minutes to a stirred solution in methanol (25 ml) of aportion (2.53 g) of the carbamate so obtained. The mixture was stirredat ambient temperature for 24 hours. The solvent was evaporated and theresidue was dissolved in water (50 ml). A 1M aqueous sodium hydroxidesolution (25 ml) was added and the mixture was stirred for 1 hour. Theprecipitate was collected, washed with water and with diethyl ether anddried. There was thus obtained 3-[1-(4-pyridyl)piperidin-4-yloxy]aniline(1.71 g), m.p. 184-186° C.;

[0386] NMR Spectrum 1.60 (m, 2H), 1.96 (m, 2H), 3.23 (m, 2H+H2O), 3.65(m, 2H) 4.48 (m, 1H), 5.00 (s, 2H), 6.16 (m, 3H), 6.82 (d, 2H), 6.88 (t,1H), 8.15 (d, 2H).

EXAMPLE 17

[0387] Diethyl azodicarboxylate (0.157 ml) was added over 15 minutes toa stirred mixture of 1-(4pyridyl)piperidin-4-ol (0.178 g),4-(4-chlorophenylsulphonyl)phenol (J. Amer. Chem. Soc., 1956, 78, 3400;0.269 g), triphenylphosphine (0.265 g) and THF (10 ml) which had beencooled to 4° C. The resultant mixture was stirred for 42 hours atambient temperature. The solvent was evaporated and the the residue waspurified by column chromatography using a 9:1 mixture of methylenechloride and methanol as eluent. The residue was triturated underdiethyl ether to give4-[4-chlorophenylsulphonyl)phenoxy]-1-(4-(pyridyl)piperidine (0.134 g),m.p. 151-152° C.;

[0388] NMR Spectrum 1.68 (m, 2H), 2.02 (m, 2H), 3.24 (m, 2H+H2O), 3.67(m, 2H), 4.78 (m, 1H), 6.81 (d, 2H), 7.17 (d, 2H), 7.65 (d, 2H), 7.89(m, 4H), 8.13 (d, 2H);

[0389] Mass Spectrum m/z 429/431 (M+H);

[0390] Elemental Analysis Found C, 60.6; H, 4.8; N, 6.6; C22H21ClN2O3S0.5H2O requires C, 60.3; H, 5.1; N, 6.4%.

EXAMPLE 18

[0391] N-(4-Pyridyl)piperazine (0.163 g) was added, in one portion, to astirred solution of 5-(6-bromonaphth-2-ylsulphonyl)phthalic anhydride(0.417 g.) in DMF (10 ml.) and the mixture was stirred at ambienttemperature for 1 hour. Diethyl ether (40 ml.) was added and the mixturewas stirred rapidly. The resultant white, amorphous precipitate wasrecovered by filtration. There was thus obtained a 1:1 mixture (0.474g., 81%) of:—

[0392]5-(6-bromonaphth-2-ylsulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylcarbonyl]benzoicacid and4-(6-bromonaphth-2-ylsulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylcarbonyl]benzoicacid; the mixture giving the following characterising data;

[0393] NMR Spectrum 3.2-3.8 (m, 16H), 6.8 (m, 4H), 7.5 (d, 1H), 7.8-7.9(m, 3H), 8.0 (m, 2H), 8.05 (s, 2H), 8.1-8.25 (m, 10H), 8.4 (d, 2H), 8.45(d, 1H), 8.8 (s, 1H);

[0394] Mass Spectrum m/z 579 (M+H);

[0395] Elemental Analysis Found C, 52.9; H, 4.5; N, 6.8; C27H22BrN3O5S2H2O requires C, 52.6; H, 4.3; N, 6.8%.

[0396] The 5-(6-bromonaphth-2-ylsulphonyl)phthalic anhydride used as astarting material was prepared as follows:—

[0397] Triethylamine (3.1 ml) was added dropwise to a stirred mixture of5-bromophthalic anhydride (5-bromo-1,3-dihydro-2-benzofuran-1,3-dione;4.54 g), 6-bromo-2-naphthalenethiol (European Patent Application No.0409413, Example 19; 5.25 g) and DMF (50 ml) and the mixture was stirredat ambient temperature for 10 minutes. The mixture was heated at 60° C.for 1 hour and then stirred at ambient temperature for 16 hours. Thesolvent was evaporated and the residue was suspended in methanol (60ml). The mixture was basified by the addition of 2M aqueous sodiumhydroxide solution and the mixture was heated to reflux for 1 hour. Themixture was cooled ambient temperature and partitioned between water(300 ml) and diethyl ether. The aqueous layer was acidified by theaddition of concentrated hydrochloric acid and extracted with ethylacetate (2×100 ml). The combined extracts were washed with water andwith brine, dried (MgSO4) and evaporated. The residue was trituratedunder diethyl ether to give 4-(6-bromonaphth-2-ylthio)phthalic acid (6g, 74%) as a pale yellow solid;

[0398] NMR Spectrum (CDCl₃/DMSO) 7.02 (m, 1H), 7.18 (m, 1H), 7.2-7.55(m, 5H), 7.65 (s, 1H), 7.72 (s, 1H).

[0399] A portion (4.5 g) of the material so obtained was suspended inglacial acetic acid (50 ml.) and sodium perborate tetrahydrate (5.13 g)was added in small portions. The reaction mixture was then stirred atambient temperature for 16 hours. A further portion (1.72 g) of sodiumperborate tetrahydrate was added and the mixture was stirred for afurther 6 hours. The reaction mixture was poured into water (500 ml.)and extracted with ethyl acetate. The extracts were washed with waterand with brine, dried (MgSO4) and evaporated to give4-(6-bromonaphth-2-ylsulphonyl)phthalic acid as a white solid (5.31 g);

[0400] NMR Spectrum 7.85 (m, 2H), 8.0 (m, 1H), 8.1-8.3 (m, 4H), 8.35 (d,1H), 8.8 (s, 1H).

[0401] A mixture of a portion (0.538 g) of the material so obtained wassuspended in acetic anhydride (5 ml) and the mixture was heated to 100°C. until a clear solution was obtained. The mixture was cooled toambient temperature. The resultant white solid was recovered byfiltration, washed with diethyl ether and dried to give5-(6-bromonaphth-2-ylsulphonyl)-phthalic anhydride (0.362 g);

[0402] Mass Spectrum m/z 416 (M+H).

[0403] Elemental Analysis Found C, 52.0; H, 2.1; C18H9BrO5S requires C,51.8; H, 2.17%.

EXAMPLE 19

[0404] To a solution of 4-((4-(4-pyridyl)piperazin-1-ylmethyl)benzoicacid chloride (510 mg) in dichloromethane (20 ml) was addedtriethylamine (1 ml), followed by a solution of4-(4-chlorophenoxy)aniline (265 mg). The resulting mixture was stirredat room temperature for 18 hours. The mixture was partitioned betweenwater and dichloromethane. The organic extracts were dried (MgSO₄) andevaporated to give a gum which was purified by column chromatography onsilica eluting with increasing concentrations of methanol anddichloromethane togivel-[4-(4-(4-chlorophenoxy)phenylaminocarbonyl)benzyl]-4-(4-pyridyl)piperazineas a glass (32 mg);

[0405] NMR Spectrum 8.15 (d, 2H), 7.95 (d, 2H), 7.8 (d, 2H)7.4-7.5 (m,4H), 6.95-7.1 (m, 4H), 6.85 (d, 2H), 3.6 (s, 2M), 3.2-3.4 (m, 8H);

[0406] Mass Spectrum m/z 499 (M+H)⁺;

[0407] Elemental Analysis Found C, 66.3; H, 5.4; N, 10.7;C₂₉H₂₇ClN₄O₂.1.5H₂O requires C, 66.2; H, 5.7; N, 10.65%.

[0408] The acid chloride used as a starting material was prepared asfollows:—

[0409] (a) To a suspension of 4-(4-pyridyl)piperazine (13.1 g) in ethylacetate (200 ml) was added triethylamine (56 ml) followed dropwise, over5 hours, by a solution of methyl 4-bromomethylbenzoate (18.41 g). Themixture was stirred at room temperature for 18 hours. The mixture waspartitioned between water and ethyl acetate. The organic extracts weredried (MgSO₄) and evaporated to give a gum, which was purified by columnchromatograhy on silica eluting with increasing concentrations ofmethanol/dichloromethane to give methyl4-(4-(4-pyridyl)piperazin-1-ylmethyl)benzoate (13.1 g) as a solid;

[0410] NMR Spectrum 8.15 (d, 2H), 7.95 (d, 2H), 7.5 (d, 2H), 6.8 (d,2H), 3.85 (s, 3H), 3.6 (s, 2H), 3.25-3.35 (m, 4H), 2.45-2.55 (m, 4H);

[0411] Mass Spectrum m/z 311 (M+H)⁺;

[0412] Elemental Analysis Found C, 69.2; H, 6.6; N, 13.5 C₁₈H₂₁N₃O₂requires C, 69.4; H, 6.8; N, 13.5%.

[0413] (b) To a solution of the product of step (a) (849 mg) in methanol(15 ml) was added 2N sodium hydroxide (6.8 ml) and the resulting mixturewas stirred for 3 hours. The mixture was evaporated to dryness. Theresulting gum was dissolved in water (7 ml) and acidified with aceticacid. The mixture was filtered to give4-(4-(4-pyridyl)piperazin-1-ylmethyl)benzoic acid (429 mg);

[0414] NMR Spectrum (CD₃SOCD₃+CD₃COOD) 8.15 (d, 2H), 8.0 (d, 2H), 7.5(d, 2H), 7.1 (d, 2H), 3.7-3.8 (m, 6H), 2.7-2.8 (m, 4H);

[0415] Mass Spectrum m/z 298 (M+H)⁺;

[0416] Elemental Analysis Found C, 68.3; H, 6.4; N, 14.0; C₁₇H₁₉N₃O₂requires: C, 68.7; H, 6.4; N, 14.1%.

[0417] (c) To a suspension of the product from step (b) (5.19 g) indichloromethane (100 ml) was added thionyl chloride (7.3 ml). Theresulting mixture was stirred for 3 hours and then evaporated to givethe acid chloride as a solid (7.66 g) which was used without furtherpurification.

EXAMPLE 20

[0418] To a solution of 2-[1-(4-pyridyl)piperidin-4-ylmethoxy]aniline(131 mg) in pyridine (5 ml) was added 6-bromonaphthyl-2-sulphonylchloride (148 mg). The resulting mixture was heated to 120° C. for 18hours. The mixture was concentrated to a gum, which was purified bycolumn chromatography on silica eluting with increasing concentrationsof methanol and dichloromethane to give6-bromo-N-{2-[-(4-pyridyl)piperidin-4-ylmethoxy]phenyl}-2-naphthalenesulphonamide(177 mg), m.p. 197-200° C.;

[0419] NMR Spectrum 8.15 (s, 2H), 8.0-8.1 (m, 4H), 7.8 (dd, 1H), 7.55(dd, 1H), 7.3 (dd, 1H), 7.05-7.1 (m, 1H), 6.8-6.9 (m, 2H), 6.7 (d, 2H),3.7 (d, 2H), 3.3-3.4 (m, 2H), 2.4-2.4 (m, 2H), 1.3-1.4 (m, 3H), 0.7-0.9(m, 2H);

[0420] Mass Spectrum m/z=552/554 (M+H⁺);

[0421] Elemental Analysis Found C, 56.5; H, 4.6; N, 7.5;C₂₇H₂₆BrN₃O₃S.H₂O requires C, 56.8; H, 4.9; N, 7.4%.

[0422] The 2-[1-(4-pyridyl)piperidin-4-ylmethoxy]aniline used as astarting material was prepared as follows:—

[0423] (a) To a solution of 2-aminophenol (2.84 g) in dichloromethane(120 ml) was added di-tert-butyl dicarbonate (6.55 g). The mixture wasstirred at room temperature for 18 hours. The mixture was partitionedbetween water and dichloromethane. The organic extracts were dried(MgSO₄) and evaporated to give a solid which was purified by columnchromatography on silica eluting with a mixture of ethyl acetate andhexane (20:80) to give 2-tert-butyloxycarbonylaminophenol (1.80 g);

[0424] NMR Spectrum 9.7 (s, 1H), 7.7 (s, 1H), 7.6 (d, 1H), 6.7-6.9 (m,3H), 1.45 (s, 9H);

[0425] Mass Spectrum m/z=210 (M+H).

[0426] (b) To a solution of 1-(4-pyridyl)piperidin-4-ylmethanol (357 mg)and 2-tert-butyloxycarbonylaminophenol (328 mg) in tetrahydrofuran (15ml) was added triphenylphosphine (447 mg) followed by diethylazodicarboxylate (0.27 ml). The mixture was stirred at room temperaturefor 18 hours. The reaction mixture was concentrated to a gum which waspurified by column chromatography on silica eluting withmethanol/dichloromethane (10:90) to give the tert-butyloxycarbonylprotected derivative of 2-[1-(4-pyridyl)piperidin-4-ylmethoxy]aniline(1.05 g);

[0427] NMR Spectrum 8.2 (d. 2H), 7.5-7.7 (m, 2H), 6.95-7.05 (m, 2H), 6.8(d, 2H), 3.85-4.1 (m. 4H), 2.8-2.95 (m, 2H), 1.8-1.9 (m, 1H), 1.45 (s,9H), 1.15-1.25 (m, 5H);

[0428] Mass Spectrum m/z=384 (M+H).

[0429] (c) To a solution of the product from step (b) (1.39 g) inmethanol (50 ml) was added methanolic HCl (5 ml) and the resultingmixture was stirred for 4 days. The reaction mixture was partitionedbetween sodium bicarbonate solution and dichloromethane. The organicextracts were dried (MgSO₄) and evaporated to give2-[1-(4-pyridyl)piperidin-4-ylmethoxy]aniline as a solid (971 mg) whichwas used without further purification;

[0430] NMR Spectrum 8.1-8.15 (m, 2H), 6.6-6.8 (m, 6H), 3.74.0 (m, 6H),2.85-3.0 (m, 2H), 1.8-2.2 (m, 5H), 1.2-1.3 (m, 2H).

EXAMPLE 21

[0431] Using an analogous procedure to that described in Example 4except that the reaction mixture was stirred at ambient temperature for26 hours, 3-[1-(4-pyridyl)piperidin-4-yloxy]aniline was reacted with(E)-4-chlorostyrylsulphonyl chloride. The product was washed withmethylene chloride and dried. There was thus obtained4-chloro-N-{3-[1-(4-pyridyl)piperidin-4yloxy]phenyl}-(E)-styrylsulphonamide,hydrochloride salt, in 73% yield, m.p. 147-150 C;

[0432] NMR Spectrum 1.59 (m, 2H), 2.00 (m, 2H), 3.58 (m, 2H), 3.86 (m,2H), 4.63 (m, 1H), 6.70 (d, 1H), 6.77 (m, 2H), 7.20 (m, 3H), 7.30 (d,1H), 7.49 (m, 3H), 7.73 (d, 2H), 8.22 (d, 2H), 10.10 (bs, 1H);

[0433] Mass Spectrum m/z 470/472 (M+H);

[0434] Elemental Analysis Found C, 56.2; H 5.1; N, 8.4; C₂₄H₂₄ClN₃O₃S1HCl 0.25H₂O requires: C, 56.4; H, 5.0; N, 8.2%.

[0435] The 3-[1-(4-pyridyl)piperidin-4-yloxy]aniline used as startingmaterial was prepared in Example 16.

EXAMPLE 22

[0436] Using an analogous procedure to that described in Example 17,1-(4-pyridyl)piperidin-4-ol was reacted with4-(6-bromonaphth-2-ylsulphonyl)phenol. There was thus obtained4-[4-(6-bromonaphth-2-ylsulphonyl)phenoxy]-1-(4-pyridyl)piperidine in62% yield, m.p. 180-183° C.;

[0437] NMR Spectrum 1.62 (m, 2H), 1.97 (m, 2H), 3.24 (m, 2H+H₂O), 3.65,(m, 2H), 4.77 (m, 1H), 6.80 (d, 2H), 7.19 (d, 2H), 7.80 (d, 1H), 7.91(d, 3H), 8.05-8.19 (m, 4H), 8.34 (s, 1H), 8.70 (s, 1H);

[0438] Mass Spectrum m/z 523/525 (M+H);

[0439] Elemental Analysis Found C, 59.3; H, 4.4; N, 5.7; C₂₆H₂₃BrN₂O₃Srequires: C, 59.7; H, 4.4; N, 5.4%.

[0440] The 4-(6-bromonaphth-2-ylsulphonyl)phenol used as a startingmaterial was prepared as follows:—

[0441] Aluminium chloride (3.33 g) was added portionwise over 30 minutesto a stirred mixture of 6-30 bromonaphth-2-ylsulphonyl chloride (6.11 g)and anisole (3.33 g) in dry methylene chloride (35 ml). The resultantmixture was stirred for 24 hours. Methylene chloride (75 ml) was added,the mixture cooled to 4° C. and water (100 ml) added cautiously. Themixture was acidified with 2M hydrochloric acid, separated and theaqueous phase extracted with methylene chloride (30 ml). The combinedorganic phases were washed with water, dried (MgSO₄) and evaporated.Recrystallisation of the residue from an ethyl acetate/ethanol mixturegave 4-(6-bromonaphth-2-ylsulphonyl)anisole (1.74 g), m.p. 180-181° C.;

[0442] NMR spectrum 3.80 (s, 3H), 7.12 (d, 2H), 7.80 (d, 1H), 7.92 (m,3H), 8.08 (d, 1H), 8.16 (d, 1H), 8.32 (s, 1H), 8.69 (s, 1H);

[0443] Mass spectrum m/z 377/379 (M+H).

[0444] A 1M solution of boron tribromide in methylene chloride (9.65 ml)was slowly added to a stirred, cooled (−78° C.), methylene chloride (25ml) solution of a portion (1.21 g) of the anisole derivative soobtained. The mixture was stirred for 20 hours at ambient temperature,then cooled to −0° C., diethyl ether (4 ml) slowly added, and stirringcontinued for 10 minutes. Water (25 ml) was added and the mixtureextracted with ethyl acetate (2×25 ml). The combined organic extractswere washed with water, dried (MgSO₄) and evaporated. Trituration of theresidue under ether gave 4-(6-bromonaphth-2-ylsulphonyl)phenol (1.03 g),m.p. 178-180° C.;

[0445] NMR Spectrum 6.92 (d, 2H), 7.77-7.91 (m, 4H), 8.06 (d, 1H), 8.14(d, 1H), 8.32 (s, 1H), 8.68 (s, 1H), 10.62 (s, 1H);

[0446] Mass Spectrum m/z 361/363 (M−H);

[0447] Elemental Analysis Found C, 52.3; H, 3.2; S, 8.3; C₁₆H₁₁BrO₃S0.25H₂O requires: C, 52.3; H, 3.15; S, 8.7%.

EXAMPLE 23

[0448] 6-Bromo-2-naphthylenethiol (2.39 g) was slowly added to a stirredsuspension of sodium hydride (60% w/w suspension in mineral oil, 404 mg)in DMF (10 ml) at 4° C. After 1 hour, a portion (569 mg)4-(4-fluorobenzoyl)-1-(4-pyridyl)piperidine and furtherdimethylformamide (8 ml) were added. The mixture was stirred at 50° for24 hours and then 16 hours at ambient temperature. The mixture was addedto water (50 ml) and extracted with methylene chloride (3×50 ml). Thecombined organic extracts were washed with water, dried (Mg SO₄) andevaporated. The residue was purified by column chromatography usingincreasingly polar mixtures of methanol and methylene chloride aseluent. There was thus obtained4-[4-(6-bromonaphth-2-ylthio)benzoyl]-1-(4-pyridyl)piperidine (613 mg);

[0449] NMR Spectrum (CDCl₃) 1.70-2.02 (m, 4H+H₂O), 3.03 (td, 2H), 3.43(m, 1H), 3.92, (dm, 2H), 6.68 (d, 2H), 7.25 (s, 2H), 7.51 (d, 1H), 7.60(d, 1H), 7.67 (d, 1H), 7.77 (d, 1H), 7.84 (d, 2H), 8.01 (d, 2H), 8.25(bs, 2H);

[0450] Mass Spectrum m/z 503/505 (M+H).

[0451] The 4-(4- fluorobenzoyl)-1-(4-pyridyl)piperidine used as astarting material was prepared as follows:—

[0452] A stirred mixture of 4-(4-fluorobenzoyl)piperidine, hydrochloridesalt (3.90 g), 4-chloropyridine, hydrochloride salt (2.85 g) andtriethylamine (4.90 ml) in xylene (75 ml) was heated at 145° C. for 27hours. The solvent was evaporated and the residue partitioned betweenmethylene chloride (150 ml) and water (100 ml), the pH being adjusted to10 with 0.880 ammonia. The aqueous phase was extracted with a furthermethylene chloride (50 ml). The combined organic phases were washed withwater, dried (Mg SO₄) and evaporated. The residue was purified by columnchromatography using a 19:1 mixture of methylene chloride and methanolas eluent to give 4-(4- fluorobenzoyl)-1-(4-pyridyl)piperidine (1.89 g);

[0453] NMR Spectrum (CDCl₃) 1.80-2.06 (m, 4H+H₂O), 3.03 (t, 2H), 3.48(m, 11H), 3.94, (d, 2H), 6.68 (d, 2H), 7.18 (t, 2H), 8.01 (m, 2H), 8.28(d, 2H);

[0454] Mass Spectrum m/z 285 (M+H).

EXAMPLE 24

[0455] Sodium perborate tetrahydrate (614 mg) was added to a stirredsolution of4-[4-(6-bromonaphth-2-ylthio)benzoyl]-1-(4-pyridyl)piperidine (505 mg)in glacial acetic acid (25 ml). After 4 hours further sodium perboratetetrahydrate (614 mg) was added and stirring continued for 27 hours. Thereaction mixture was poured into an ice/water mixture (50 ml) andextracted with methylene chloride (4×25 ml)., The combined extracts werewashed with water and with brine, dried (Mg SO₄) and evaporated. Theresidue was purified by column chromatography using a 19:1 methylenechloride and methanol mixture as eluent and the resultant foamtriturated under is-hexane. There was thus obtained4-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]-1-(4-pyridyl)piperidine (21mg);

[0456] NMR Spectrum (CDCl₃) 1.77-2.05 (m, 4H), 3.15 (td, 2H), 3.52 (m,1H), 4.00, (m, 2H), 6.71 (d, 2H), 7.72 (dd, 1H), 7.85 (m, 3H), 8.08 (m,5H), 8.24 (d, 2H), 8.57 (s, 1H);

[0457] Mass Spectrum m/z 535/537 (M+H).

EXAMPLE 25

[0458] A stirred mixture of 4-chloropyridine hydrochloride (78.3 mg),1-[4-(6-bromonaphth-2-ylsulphonyl)phenylsulphonyl]piperazinehydrochloride (185 mg), triethylamine (0.145 ml) and xylene (3.0 ml) washeated at 140° C. for 16 hours. The solvent was evaporated and theresidue purified by column chromatography on a C-18 60 Å preparativereversed-phase HPLC column using 0.1% trifluoroacetic acid in aqueousacetonitrile and a gradient of 30% to 70% acetonitrile. There was thusobtained4-[4-(6-bromonaphth-2-ylsulphonyl)phenylsulphonyl]-1-(4-pyridyl)piperazine,trifluoroacetate salt (29.1 mg), m.p. 236-238° C.:

[0459] NMR Spectrum 3.10 (t, 4H), 3.74 (t, 4H), 7.10 (d, 2H), 7.82 (d,1H), 7.98 (d, 3H), 8.08-8.29 (m, 6H), 8.36 (s, 1H), 8.78 (s, 1H);

[0460] Mass Spectrum m/z 572/574 (M+H).

[0461] The 1-[4-(6-bromonaphth-2-ylsulphonyl)phenylsulphonyl]piperazineused as a starting material was prepared as follows:—

[0462] 4-Fluorobenzenesulphonyl chloride (1.95 g) was added to a stirredsolution of N-=-butyloxycarbonylpiperazine (1.86 g) and triethylamine(6.9 ml) in methylene chloride (100 ml) at 4° C. and stirring continuedat ambient temperature for 16 hours. The solvent was evaporated and theresidue purified by column chromatography using methylene chloride and1% methanol in methylene chloride as eluent. There was thus obtained4-(4-fluorophenylsulphonyl)-1-(tert-butyloxycarbonyl)piperazine (3.09g), m.p. 163-164° C.;

[0463] NMR Spectrum (CDCl₃) 1.42 (s, 9H), 2.98 (t, 4H), 3.51 (t, 4H),7.23 (m, 2H), 7.77 (m, 2H);

[0464] Mass Spectrum m/z 362 (M+NH₄);

[0465] Elemental Analysis Found C, 52.1; H, 6.1; N, 8.0; C₁₅H₂₁FN₂O₄Srequires: C, 52.3; H, 6.15; N, 8.1%.

[0466] Sodium hydride (60% w/w suspension in mineral oil, 88 mg) wasslowly added to a stirred solution of 6-bromo-2-naphthylenethiol (478mg) in dry DMF (5 ml) at 4° C. and stirring continued for 30 minutes. Aportion of the piperazine derivative (688 mg) prepared in the previousparagraph was added and stirring continued for 1 hour at 4° C. and for64 hours at ambient temperature. The mixture was added to an ice/watermixture and the precipitated solid collected by filtration. Purificationby column chromatography using initially a 10% then a 15% mixture ofethyl acetate and iso-hexane as eluent gave4-[4-(6-bromonaphth-2-ylthio)phenylsulphonyl]-1-(=-butyloxycarbonyl)piperazine(630 mg), m.p. 99-101° C.;

[0467] NMR Spectrum (CDCl₃) 1.42 (s, 9H), 2.97 (t, 4H), 3.49 (t, 4H),7.25 (m, 2H), 7.5-7.8 (m, 6H) 8.06 (d, 2H);

[0468] Mass Spectrum m/z 507/509 (M+H—C₄H₈);

[0469] Elemental Analysis Found C, 53.6; H, 5.1; N, 5.0; C₂₅H₂₇BrN₂O₄S₂requires: C, 53.3; H, 4.8; N, 5.0%.

[0470] Sodium perborate tetrahydrate (308 mg) was added to a stirredsolution of a portion (282 mg) of the material prepared above in glacialacetic acid (2 ml). After stirring for 16 hours, further acetic acid (2ml) and sodium perborate tetrahydrate (308 mg) were added, stirringcontinued for 16 hours when a final addition of acetic acid (10 ml) andsodium perborate tetrahydrate (308 mg) was made. After stirring for afurther 16 hours the reaction mixture was poured into an ice/watermixture. The precipitated solid was isolated giving4-[4-(6-bromonaphth-2-ylsulphonyl)phenylsulphonyl]-1-(=-butyloxycarbonyl)piperazine(295 mg), m.p. 213-215° C., which was used without further purification.

[0471] A solution of the material so obtained (295 mg) in methylenechloride (10 ml) was treated with a 2.2M solution of hydrogen chloridein diethyl ether (1.2 ml). The mixture was stirred at ambienttemperature for 48 hours. The precipitated solid was collected byfiltration and washed with methylene chloride giving1-[4-(6-bromonaphth-2-ylsulphonyl)phenyl-sulphonyl]piperazinehydrochloride salt, (205 mg), m.p. 250-260° C. (decomposition);

[0472] NMR Spectrum 3.12 (s, 8H), 7.83 (d, 1H), 8.01 (m, 3H), 8.15 (d,1H), 8.20 (d, 1H), 8.28 (d, 2H), 8.36 (s, 1H), 8.81 (s, 1H), 8.98 (bs,2H);

[0473] Mass Spectrum m/z 495/497 (M+H).

EXAMPLE 26

[0474] To a solution of 6-(bromo-2-(4-(2-aminoethylaminocarbonyl)phenylsulphonyl)naphthalene (400 mg) in ethanol (15 ml) was added4-chloropyrimidine hydrochloride (131 mg) and triethylamine (294 mg).The mixture was heated to reflux for 3 hours. Further portions of4-chloropyrimidine (131 mg) and triethylamine (108 mg) were added andheating continued for a further 1 hour.

[0475] After cooling, the reaction mixture was diluted with ethylacetate (100 ml.), washed with water (2×25 ml) and brine (25 ml), dried(MgSO4) and evaporated to give a solid. This was purified bychromatography on a Mega Bond Elut silica column, eluting withdichloromethane containing increasing proportions of methanol (0%-5%) togive6-(bromo-2-(4-(2-pyrimidin-4-yl)aminoethylaminocarbonyl)phenylsulphonyl)naphthalene(140 mg);

[0476] NMR spectrum 3.3-3.5 (m, 4H); 6.45 (m, 1H); 7.3-7.5 (m, 1H); 7.8(dd, 1H); 7.9-8.05 (m, 4H); 8.05-8.2 (m, 3H)1; 8.25 (d, 1H); 8.4 (d,2H); 8.8 (s, 2H);

[0477] Mass spectrum m/z 511 (m+H);

[0478] Elemental Analysis Found C: 50.2;.H: 3.7; N: 10.0; C23H19BrN4O3S.0.6 CH2Cl2 requires C: 50.4; H: 3.6; N: 9.9.

[0479] The6-(bromo-2-(4-(2-aminoethylaminocarbonyl)phenylsulphonyl)naphthaleneused as starting material may be prepared as follows.

[0480] i) To a suspension of sodium hydride 48% dispersion (960 mg, 20mmol) in dimethylformamide (50 ml), cooled to 5° C. and stirred undernitrogen, was added in small portions 6-bromonaphthalene-2-thiol (4.78g, 20mmol). The mixture was allowed to warm to ambient temperature over1 hour. 4-Fluorobenzonitrile (2.66 g, 22 mmol) was then added, themixture heated to 90° C. for a further 1 hour and then poured into water(600 ml). The resulting solid was purified by recrystallisation frommethanol to give 6-(bromo-2-(4-cyanophenylthio)naphthalene (5.7 g);

[0481] NMR Spectrum 7.3 (dd, 2H); 7.55 (dd, 0.1H); 7.7-7.8 (m, 314); 7.9(d, 1H); 8.0 (d, 1H); 8.2 (s, 1H); 8.3 (s, 11H).

[0482] (ii) A mixture of the product from i) above (5.7 g), potassiumhydroxide (3 g), water (I 5 ml) and ethylene glycol (100 ml.).was heatedto 160° C. for 7 hours. After cooling to ambient temperature the mixturewas diluted with water (500 ml.), acidified with concentrated HCl (pH 2)and extracted with ethyl acetate (2×200 ml). The combined extracts werewashed with water (2×100 ml) and brine (100 ml), dried (MgSO4) andevaporated to give 4-(6-bromonaphth-2-ylthio)benzoic acid (5.3 g);

[0483] NMR Spectrum 7.2 (dd, 2H); 7.5 (dd, 1H); 7.7 (dd, 2H); 7.9 (dd,2H); 7.95 (d, 1H); 8.0 (d, 1H); 8.1 (s, 1H); 8.2 (s, 1H);

[0484] Mass Spectrum m/z 357 m−H.

[0485] (iii) The acid from ii) above (5.3 g) was suspended in glacialacetic acid (100 ml). Sodium perborate (9 g) was added and the mixturestirred at ambient temperature for 24 hours. A further portion of sodiumperborate (9 g) was added and the mixture heated to 55° C. for 6 hours.After cooling to ambient temperature, water (200 ml) was added and theresulting white solid precipitate recovered by filtration to give4-(6-bromonaphth-2-ylsulphonyl)benzoic acid (4.1 g);

[0486] NMR Spectrum 7.8-7.9 (m, 2H); 7.95 (d, 1H); 8.05-8.15; (m, 4H);8.2 (d, 1H); 8.3 (s, 1H); 8.8 (s, 1H);

[0487] iv) The acid from iii) above (7.16) was dissolved indimethylformamide (100 ml.). N-hydroxysuccinamide (2.88 gm) was addedand the mixture cooled to 5° C. EDAC (4.2 g) was added in one portionand the mixture stirred 16 hours at ambient temperature. Ethyl acetate(50 ml) was added and after washing with water (3×100 ml.) and brine(100 ml.) the reaction mixture was evaporated to give a white solid.This was further purified by flash column chromatography on silica gel,eluting with dichloromethane, to give the succinimide ester of the acidproduct of iii) (6.3 g), mp 287-290° C.;

[0488] NMR Spectrum (CDCl₃) 2.9 (s, 4H); 7.7 (dd, 1H); 7.8-7.9 (m, 3H);8.1 (s, 1H); 8.15 (d, 2H); 8.25 (d, 2H); 8.6 (s, 1H);

[0489] Mass Spectrum m/z 389 m−H.

[0490] v) The ester from iv) above (976 mg) was treated with N-BOCethylenediamine (320 mg) in dimethylformamide (10 ml) and stirred atambient temperature for 18 hours. After diluting with ethyl acetate (150ml), washing with 2M sodium hydroxide (2×25 ml), 1M citric acid (25 ml),water (25 ml) and brine (25 ml), the reaction mixture was dried (MgSO4)and evaporated to give the tert-butoxycarbonyl derivative of the desiredstarting material as a white solid. This was dissolved in trifluroaceticacid (5 ml), stirred at ambient temperature for 2 hours and thenevaporated to give an oil. Ether (50 ml) was added and the mixturestirred vigorously to give6-(bromo-2-(4-(2-aminoethylaminocarbonyl)phenylsulphonyl)naphthalene asa white solid which was recovered by filtration (893 mg);

[0491] NMR spectrum 2.95 (t, 2H); 3.4-3.5 (m, 2H); 7.7-7.9 (m, 4H); 7.95(dd, 1H); 8.1 (d, 2H); 8.15-8.25 (m, 4H); 8.35 (s, 1H); 8.75-8.85 (m,2H);

[0492] Mass spectrum m/z 433 m+H;

[0493] Elemental Analysis Found C: 45.6; H: 3.1; N: 5.2; C19H17BrN2O3S.1.1 TFA requires C: 45.6; H: 3.27; N: 5.01.

EXAMPLE 27

[0494] A mixture of the acid from part (ii) of Example 26 (358 mg),hydroxybenztriazole (202 mg), N-(4-pyridyl)piperazine (163 mg) and EDAC(210 mg) was dissolved in dimethylformamide (10 ml) and stirred atambient temperature for 1 hour. Water (50 ml) and 2M sodium hydroxide(10 ml) was added and the mixture extracted with ethyl acetate (2×50ml.). After washing the combined extracts with water (2×20 ml), drying(MgSO4) and evaporating1-[4-(6-bromonaphth-2-ylthio)benzoyl]-4-(4-pyridyl)piperazine wasobtained as a white solid. (345 mg), mp 210-213 C;

[0495] NMR Spectrum CDCl₃ 3.2-3.4 (m, 4H); 3.6-4.0 (m, 4H); 6.7 (dd,2H); 7.3-7.4 (m, 4H); 7.45 (d, 1H), 7.5-7.7 (m, 2H); 7.75 (d, 1H); 7.9(s, 1H); 8.0 (s, 1H); 8.3 (d, 2H);

[0496] Mass Spectrum m/z 504 m+H;

[0497] Elemental Analysis Found C: 61.8; H: 4.6; N: 8.3; C26H22BrN30SRequires C: 61.9; H: 4.4; N: 8.3.

EXAMPLE 28

[0498] A mixture of the acid from part (iii) of Example 26 (782 mg),hydroxybenztriazole (297 mg), N-(4-pyridyl)piperazine (326 mg) and EDAC(382 mg) was dissolved in dimethylformamide (15 ml) and stirred atambient temperature for 4 hours. Ethyl acetate (100 ml) was added andafter washing with water (2×25 ml) and brine (25 ml) the reactionmixture was evaporated to give a solid. Purification by columnchromatography on silica gel (Mega Bond Elut),eluting withdichloromethane containing an increasing proportion of methanol (0-5%),gave as a solid1-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]-4-(4-pyridyl)piperazine (120mg);

[0499] NMR Spectrum CDCl₃/TFA 3.5-4.0 (b, 8H); 6.9 (d, 2H); 7.6 (d, 2H);7.7 (dd, 1H); 7.8-7.9 (m, 3H); 8.0-8.1 (m, 3H); 8.15-8.25 (m, 2H); 8.55(s, 1H);

[0500] Mass Spectrum m/z 536 m+H.

[0501] Elemental Analysis Found C: 57.2; H: 4.5; N: 7.4;C26H22BrN3O3S.0.5H₂O Requires C: 57.3; H: 4.3; N: 7.7.

EXAMPLE 29

[0502] A mixture of the acid from part (iii) of Example 26 (391 mg),hydroxybenztriazole (202 mg), N-(4-pyrimidyl)piperazine (326 mg) andEDAC (202 mg) was dissolved in dimethylformamide (10 ml) and stirred atambient temperature for 3 hours. Ethyl acetate (50 ml) was added andafter washing with 2M sodium hydroxide (15 ml), water (2×15 ml) andbrine (15 ml) the reaction mixture was evaporated and the residuetriturated with methanol to give a solid1-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]-4-(4-pyrimidinyl)-piperazine(391 mg);

[0503] NMR Spectrum 3.2-3.9 (m, 8H); 6.8 (d, 1H); 7.7 (d, 2H); 7.85 (dd,1H); 8.0 (dd, 1H); 8.1-8.25 (m, 5H); 8.4 (s, 1H); 8.5 (s, 1H); 8.8 (s,1H);

[0504] Mass Spectrum m/z 537 m+H;

[0505] Elemental Analysis Found C: 55.5; H: 4.0; N: 10.4; C25H21BrN4O3SRequires C: 55.9; H: 3.9; N: 10.4.

EXAMPLE 30

[0506] A mixture of N-(4-pyridazinyl)piperazine trifluroacetate (278mg), triethylamine (303 mg), N-hydroxysuccinimide ester from part (iv)of Example 26 (1 mmol) and dimethylformamide (10 ml) was stirred atambient temperature for 18 hours. The reaction mixture was evaporatedand the residue dissolved in ethyl acetate, washed with 2M sodiumhydroxide (2×25 ml), water (2×25 ml) and brine (25 ml). After drying(MgSO4), evaporation and trituration with methanol and ether,1-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]4-(4-pyridazinyl)piperazinewas obtained as a white solid 420 mg);

[0507] NMR Spectrum 3.3-3.8 (m, 8H); 6.9 (dd, 1H); 7.7 (d, 2H); 7.85(dd, 1H); 8.0 (dd, 1H); 8.1 (d, 2H);

[0508] 8.15 (d, 1H); 8.2 (d, 1H); 8.4 (s, 1H); 8.6 (d, 1H); 8.8 (s, 1H);8.9 (d, 1H);

[0509] Mass Spectrum m/z 537 m+H;

[0510] Elemental Analysis Found C: 55.1; H: 3.8; N: 10.0;C25H21BrN4O3S.0.5H2O Requires C: 55.0; H: 4.06; N: 10.3.

EXAMPLE 31

[0511] To 4-(6-bromonaphth-2-ylsulphonyl)-2-trifluoromethylbenzoic acid(1.02 g) was added thionyl chloride (10ml) and dimethylformamide (1drop). The mixture was heated on a steam bath for 30 minutes and thenevaporated to give a yellow solid which was redissolved indichloromethane (10 ml) and added to an ice cooled solution ofN-(4-pyridyl)piperazine (363 mg) and triethylamine (1.16 g) indichloromethane (10 ml). The mixture was allowed to warn to ambienttemperature and stirred for 3 hours. Water (100 ml) was added and themixture extracted with ethyl acetate (3×50 ml). The combined extractswere washed with water (3×25 ml) and brine (25 ml), dried (MgSO4) andevaporated to give a solid which was further purified by flash columnchromatography on silica gel, eluting with dichloromethane containingincreasing proportions of methanol (0-5%) to give a solid.Recrystallisation from methanol gave1-[4-(6-bromonaphth-2-ylsulphonyl-2-trifluoromethylbenzoyl]-4-(4-pyridyl)piperazine(649 mg), mp 221-223° C.;

[0512] NMR Spectrum 3.0-3.5 (m, 6H); 3.6-3.8 (m, 2H); 6.75 (d, 2H); 7.8(dd, 2H); 8.0-8.2 (m, 5H); 8.3-8.4 (m, 3H); 8.85 (s, 1H);

[0513] Mass Spectrum m/z 604 m+H;

[0514] Elemental Analysis Found C: 53.5; H: 3.5; N: 7.0; C27H21BrF3N3O3SRequires C: 53.7; H: 3.5; N: 6.95.

[0515] 4-(6-Bromonaphth-2-ylsulphonyl-2-trifluoromethylbenzoic acid usedas starting material may be prepared as follows.

[0516] i) A mixture of 6-bromonaphthalene-2-thiol (956 mg) and4-fluoro-2-trifluoromethyl benzonitrile (756 mg) in dimethylformamide(15 ml), at ambient temperature, was treated dropwise with triethylamine(504 mg). After stirring at ambient temperature for 3 hours the reactionmixture was diluted with ethyl acetate (100 ml), washed with water (3×25ml) and brine (25 ml), dried (MgSO4) and evaporated to give a yellowoil. Crystallisation from methanol (20 ml) gave4-(6-bromonaphth-2-ylthio)-2-trifluoromethylbenzonitrile (1.176 g, mp114-116° C.;

[0517] NMR Spectrum 7.4 (d, 1H); 7.6 (d, 1H); 7.75 (m, 2H); 7.9-8.1 (m,3H); 8.3 (s, 2H);

[0518] Mass Spectrum m/z 407 m⁺;

[0519] Elemental Analysis Found C: 53.1; H: 2.2; N: 3.4; C18H9BrF3NSRequires C: 53.0; H: 2.2; N: 3.4.

[0520] ii) A mixture of nitrile from (i) above (1.0 g), potassiumhydroxide (0.6 g), water (3 ml) and ethylene glycol (20 ml) was heatedat 155° C. for 24 hours. The mixture was cooled to ambient temperature,diluted with water (100 ml), washed with ether (2×50 ml) and acidifiedto pH 2 with 2M HCl and extracted with ethyl acetate (3×50 ml). Thecombined extracts were washed with water (2×50 ml) and brine (50 ml),dried (MgSO4) and evaporated to give4-(6-bromonaphth-2-ylthio)-2-trifluoromethylbenzoic acid as a solid (576mg);

[0521] Mass Spectrum m\z 425 m−H.

[0522] The acid from (ii) above (1 g) was suspended in glacial aceticacid (20 ml). Sodium perborate (1.43 g) was added and the mixturestirred at ambient temperature for 24 hours. After cooling to ambienttemperature, water (100 ml) was added and the product extracted withethyl acetate (2×50 ml). The combined extracts were washed with water(3×20 ml) and brine (20 ml), dried (MgSO4) and evaporated to give4-(6-bromonaphth-2-ylsulphonyl-2-trifluoromethylbenzoic acid (1.0 g);

[0523] NMR Spectrum 7.8 (dd, 1H); 7.9-8.1 (m, 2H); 8.1-8.2 (m, 2H);8.3-8.4 (m, 3H); 8.55 (s, 1H);

[0524] Mass Spectrum m/z 457 m−H.

EXAMPLE 32

[0525] To the acid from part (ii) of Example 31 (519 mg) indimethylformamide (10 ml) was added carbonyl diimidazole (196 mg). Afterstirring at ambient temperature for 30 minutes N-(4-pyridyl)piperazine(198 mg) was added and stirring continued for 24 hours. The reactionmixture was diluted with ethyl acetate (100 ml), washed with water (2×50ml) and brine (25 ml), dried (MgSO4) and evaporated to give an oil whichwas further purified by chromatography on silica gel (Mega Bond Elutcolumn, eluted with dichloromethane containing increasing proportions ofmethanol, 0-4%) to give1-[4-(6-bromonaphth-2-ylthio)-2-trifluoromethylbenzoyl]-4-(4-pyridyl)piperazine(128 mg);

[0526] NMR Spectrum 3.2 (m, 4H); 3.4 (m, 4H); 3.7 (m, 2H); 6.8 (md, 2H);7.4-7.8 (m, 5H); 7.95 (d, 1H); 8.0 (d, 1H); 8.1-8.2 (m, 3H); 8.3 (s,1H);

[0527] Mass Spectrum m\z 572 m+H;

[0528] Elemental Analysis Found C: 56.7; H: 3.9; N: 7.2; C27H21BrF3N30SRequires C: 56.7; H: 3.7; N: 7.3

EXAMPLE 33

[0529] 4-(6-Bromonaphth-2-ylthio)-2-carboxybenzoic acid (200 mg) wassuspended in acetic anhydride (5 ml) and heated to 120° C. for 1 hour.The precipitate of the anhydride that was obtained on cooling wasrecovered by filtration, washed with hexane and suspended indimethylformamide (2 ml). N-(4-Pyridyl)piperazine (76 mg) was added andthe mixture stirred at ambient temperature for 3 hours. Ether (20 ml)was added with vigourous stirring and the resulting white solidprecipitate was recovered by filtration, washed with ether and dried invacuo to give1-[4-(6-bromonaphth-2-ylthio)-2-carboxybenzoyl]-4-(4-pyridyl)piperazineand1-[5-(6-bromonaphth-2-ylthio)-2-carboxybenzoyl]-4-(4-pyridyl)piperazine(80 mg) as a mixture of two isomers;

[0530] NMR Spectrum 3.1-4.0 (m, 16H); 6.7-6.9 (m, 4H); 7.1 (s, 1H); 7.25(d, 1H); 7.3 (d, 1H); 7.4-7.6 (m, 3H); 7.7 (d, 2H); 7.75 (s, 1H);7.8-8.0 (m, 6H); 8.05-8.2 (m, 5H); 8.3 (s, 2H);

[0531] Mass Spectrum m\z 548 m+H.

EXAMPLE 34

[0532] 5-(6-Bromonaphth-2-ylsulphonyl)-2-methoxycarbonylbenzoic acid (97mg) was dissolved in dichloromethane (1 ml.). Oxalyl chloride (126 mg)was added and the mixture stirred at ambient temperature for 1 hour. Themixture was evaporated to give a solid which was redissolved indichloromethane (1 ml) and added to a solution-ofN-(4-pyridyl)piperazine (34 mg) and triethylamine.(108 mg)-indichloromethane (2 ml). After stirring for 2 hours at ambienttemperature the mixture was diluted with ethyl acetate (100 ml), washedwith water (2×25 ml), dried (MgSO₄) and evaporated to give an oil, whichwas further purified by chromatography (Mega Bond Elut column, elutedwith dichloromethane containing an increasing proportion of methanol,0-5%) to give1-[5-(6-bromonaphth-2-ylsulphonyl)-2-methoxycarbonylbenzoyl]-4-(4-pyridyl)piperazine(55 mg); —

[0533] NMR Spectrum 3.1-3.2 (m, 4H); 3.4-3.5 (m, 2H); 3.7-3.75 (m, 2H);3.8 (s, 3H); 6.8 (d, 2H); 7.8 (dd, 1H); 8.0 (dd, 1H); 8.05 (s, 1H);8.1-8.2 (m, 6H); 8.4 (s, 1H); 8.8 (s, 1H);

[0534] Mass Spectrum m\z 594 m+H;

[0535] Elemental Analysis Found C: 55.7; H: 4.3; N: 6.8; C228H24BrN3O5S.0.5H2O Requires C: 55.7; H: 4.18; N: 6.96.

[0536] The benzoic acid used as starting material was prepared asfollows.

[0537] 5-(6-Bromonaphth-2-ylsulphonyl)phthalic anhydride [Example 18](208 mg) was suspended in methanol (10 ml) and heated to reflux for 2hours. The reaction mixture was evaporated and dried under vacuum togive a mixture of two isomeric esters4-(6-bromonaphth-2-ylsulphonyl)-2-methoxycarbonylbenzoic acid and5-(6-bromonaphth-2-ylsulphonyl-2-methoxycarbonylbenzoic acid (210 mg).Flash column chromatography on silica gel, eluting with a mixture ofethyl acetate/methanol/acetic acid 94/5/1, gave a sample of the singleisomer used above (97 mg);

[0538] NMR Spectrum 3.8 (s, 3H), 7.8-7.9 (m, 2H); 8.0 (dd, 1H); 8.15 (d,1H); 8.2 (d, 1H); 8.3 (dd, 1H); 8.35 (s, 1H); 8.4 (s, 1H); 8.8 (s, 1H);

[0539] Mass Spectrum m\z 449 m+H.

EXAMPLE 35

[0540] A mixture of the two isomeric esters, from the part of Example 34relating to the preparation of starting material, (449 mg) was dissolvedin dichloromethane (10 ml). Oxalyl chloride (0.4 ml) was added and themixture stirred at ambient temperature for 1 hour. The mixture wasevaporated to give a solid which was redissolved in dichloromethane (5ml.) and added dropwise to a solution of N-(4-pyridyl)piperazine (163mg) and triethylamine (504 mg) in dichloromethane (10 ml). Afterstirring for 24 hours at ambient temperature the mixture was dilutedwith ethyl acetate (100 ml), washed with water (3×25 ml) and brine (25ml), dried (MgSO4) and evaporated to give a solid, which was furtherpurified by chromatography (Mega Bond Elut column, eluted withdichloromethane containing an increasing proportion of methanol, 0-5%)to give a mixture of1-[4-(6-bromonaphth-2-ylsulphonyl)-2-methoxycarbonylbenzoyl]-4-(4-pyridyl)piperazineand1-[5-(6-bromonaphth-2-ylsulphonyl)-2-methoxycarbonylbenzoyl]-4-(4-pyridyl)piperazine(461 mg);

[0541] NMR Spectrum CDCl₃ 300 MHz 3.2-349 (m, 8H); 3.4-3.6 (m, 4H);3.8-4.0 (m, 1 OH); 6.6-6.7 (m, 2H); 6.6-6.7 (m, 2H); 7.45 (d, 1H);7.7-7.45 (m, 2H); 7.8-8.0 (m, 7H); 8.05-8.2 (m, 5H); 8.3-8.4 (m, 4H);8.5-8.6 (m, 2H); 8.7 (s, 1H);

[0542] Mass Spectrum m\z 594 m+H;

[0543] Elemental Analysis Found C: 52.9; H: 4.1; N: 6.8; C28H24BrN3O5S.0.5CH2Cl2 Requires C: 52.7; H: 3.9; N: 6.4.

EXAMPLE 36

[0544] To the isomeric mixture of acids produced in Example 18 (578 mg)was added, dimethylformamide (10 ml), hydroxybenztriazole (162 mg),2-(ethylthio)ethylamine (210 mg) and EDAC (382 mg). The mixture wasstirred at ambient temperature for 18 hours, diluted with ethyl acetate(100 ml), washed with water (3×25 ml) and brine (25 ml), dried andevaporated. The residue was purified by chromatography (Mega Bond Elutcolumn, eluted with dichloromethane containing an increasing proportionof methanol, 0-5%) to give as a mixture (420 mg) of isomers,1-[4-(6-bromonaphth-2-ylsulphonyl)-2-(2-(ethylthio)-ethylaminocarbonyl)benzoyl]-4-(4-pyridyl)piperazineand1-[5-(6-bromonaphth-2-ylsulphonyl)-2-(2-ethylthio)ethylaminocarbonyl)benzoyl]-4-(4-pyridyl)piperazine;

[0545] NMR Spectrum 1.1-1.2 (m, 3H); 2.5-2.6 (m, 4H); 3.1-3.5 (m, 8H);3.6-3.75 (m, 2H); 6.7-6.8 (m, 2H); 7.6-8.4 (m, 9H); 8.7-9.0 (m, 2H);

[0546] Mass Spectrum m\z 667 m+H;

[0547] Elemental Analysis Found C: 54.0; H: 4.6; N: 8.1; C31H31BrN4O4S2.H2O Requires C: 54.3; H: 4.8; N: 8.2.

[0548] A sample of the mixed isomers (100 mg.) was separated by HPLC, C18 ODS column eluted with an acetonitrile/water mixture, to give the5-naphthylsulphonyl isomer (29 mg).

[0549] NMR Spectrum 500 MHz CH3CN/D2O 1.08 (t, 3H); 2.4-2.5 (m, 2H);2.6-2.7 (m, 2H); 3.25-3.3 (m, 2H); 3.35-3.4 (m, 2H); 3.45-3.5 (m, 2H);3.7-3.72 (m, 4H); 6.8-6.9 (m, 2H); 7.72 (dd, 1, H); 7.78 (d, 1H); 7.85(dd, 1H); 7.91 (s, 1H); 7.95-8.0 (m, 4H); 8.07 (d, 1H); 8.18 (s, 1H);8.6 (s, 1H);

[0550] Mass Spectrum m\z 667 m+H.

EXAMPLE 37

[0551] A solution of the isomeric mixture of acids produced in Example18 (prepared in situ, 30 from the phthalic anhydride (208 mg) andN-(4-pyridyl)piperazine (81.5 mg)) in dimethylformamide (5 ml.) wastreated with carbonyl diimidazole (97.0 mg) and stirred at ambienttemperature for 30 minutes. Piperidine (63 mg) was then added. Themixture was stirred at ambient temperature for 18 hours, diluted withethyl acetate (100 ml), washed with water (3×20 ml) and brine (20 ml),dried and evaporated. The residue was purified by chromatography (MegaBond Elut column, eluted with dichloromethane containing an increasingproportion of methanol, 0-5%) to give as a mixture (210 mg) of isomers,1-[4-(6-bromonaphth-2-ylsulphonyl)-2-(piperidin-1-ylcarbonyl]-4-(4-pyridyl)piperazineand1-[5-(6-bromonaphth-2-ylsulphonyl)-2-(piperidin-1-ylcarbonyl]-4-(4-pyridyl)piperazine(210 mg);

[0552] NMR Spectrum 1.3-1.6 (m, 6H); 3.0-3.6 (m, 12H); 6.7 (d, 2H);7.6-7.7 (m1H); 7.8 (dd, 1H); 8.0-8.2 (m, 7H); 8.4 (s, 1H); 8.8 (s, 1H);

[0553] Mass Spectrum m\z 647 m+H

[0554] Elemental Analysis Found C: 58.3; H: 5.0; N: 8.8; C₃₂H₃₁BrN₄O₄S.0.5H₂O Requires C: 58.5; H: 4.9; N: 8.5.

EXAMPLE 38

[0555] 4-(Chlorosulphonyl)benzoic acid (0.75 g) was added to a solutionof 1-(3-chlorophenyl)piperazine dihydrochloride (0.90 g) intriethylamine (2.4 ml) and dichloromethane (50 ml). The reaction mixturewas stirred overnight at room temperature then concentrated in vacuo.The resulting solid was suspended in N,N-dimethylformamide (50 ml) andcarbonyl diimidazole (0.55 g) was added. The reaction mixture wasstirred for one hour at room temperature then 1-(4-pyridyl)piperazine(0.55 g, 3.4 mmol) was added. The reaction mixture was stirred for threehours, then concentrated in vacuo. The resulting solid was separatedbetween ethyl acetate (100 ml) and water (100 ml). The ethyl acetatelayer was washed with aqueous saturated sodium bicarbonate solution (100ml) then dried over magnesium sulphate, filtered and concentrated invacuo. The resulting yellow oil was subjected to chromatography (SiO₂:10%-12% MeOH/EtOAc) to yield1-[4-(4-(3-chlorophenyl)piperazin-1-ylsulphonyl)benzoyl]-4-(4-pyridyl)piperazineas a white solid (300.1 mg);

[0556] NMR Spectrum 3.08 (m, 4H), 3.42 (m, 10H) 3.75 ppm (s, 2H, 6.81(m, 3H, 6.8 (dd, 1H chlorophenyl 4-H), 6.94 (t, 1H) 7.21 (t, 1H, 7.72 &7.86 (dd, 4H, phenyl 8.18 (d, 2H);

[0557] Mass Spectrum 528 (M+H)⁺;

[0558] Elemental Analysis Found Carbon 57.8%, hydrogen 5.5%, nitrogen12.3% (Calc. for C₂₆H₂₈ClN₅O₃S.0.2EtOAc.0.8H₂O Carbon 57.7%, hydrogen5.63%, nitrogen 12.5%).

EXAMPLE 39

[0559] 4-(-Chlorosulphonyl)benzoic acid (733.0 mg) was added to asolution of 6-chloro-1,2,3,4-tetrohydroisoquinoline (558.1 mg) intriethylamine (0.46 ml) and tetrahydrofuran (20 ml). The reactionmixture was stirred for two days at room temperature then concentratedin vacuo to yield4-[6-chloro-1,2,3,4-tetrahydroisoquinolin-2-ylsulphonyl]benzoic acid asan off white solid. This was suspended in dichloromethane (30 ml) andcarbonyl diimidazole (539 mg) was added. The reaction mixture wasstirred for one hour at room temperature then 1-(4-pyridyl)piperazine(541 mg) was added. The reaction mixture was stirred overnight, thenconcentrated in vacuo. The resulting solid was separated between ethylacetate (50 ml) and water (2×100 ml). The ethyl acetate layer was driedover magnesium sulphate, filtered and concentrated in vacuo. Theresulting solid was subjected to chromatography (SiO₂: 1-5%Methanol/ethyl acetate) to yield1-[4-(6-chloro-1,2,3,4-tetrahydroisoquinolin-2-ylsulphonylbenzoyl]4-(4-pyridyl)piperazinea white solid (984.7 mg);

[0560] NMR Spectrum (CDCl₃, 300 MHz) 2.66 (t, 2H), 3.22 to 3.58 (s, 6H),3.41 (t, 2H), 3.93 (s, 2H) 4.28 (s, 2H), 6.68 (m. 2H, 6.98 (d, 1H), 7.09(s, 1H), (dd, 1H, quinoline 6-H), 7.58 and 7.90 (dd, 4H, phenyl Ar H's),8.33 (d, 2H, pyridyl 2-H & 6-H);

[0561] Mass Spectrum 497 (M+H)⁺;

[0562] Elemental Analysis Found Carbon 58.1%, hydrogen 4.8%, nitrogen10.6% (Calc. for C₂₅H₂₅ClN₄O₃S.0.25CH₂Cl₂ Carbon 58.5%, hydrogen 4.96%,nitrogen 10.8%).

[0563] The 6-Chloro-1,2,3,4-tetrahydroisoquinoline may be prepared asfollows:

[0564] i) 2-(m-Chlorophenyl)ethylamine (21.92 g) was dissolved inpyridine (250 ml) and cooled to 250° C. Tosyl chloride (40.28 g) wasadded portionwise as a solid over one hour keeping the temperature below5° C. The reaction mixture was stirred for two hours at room temperaturethen concentrated in vacuo. The resulting oil was dissolved indichloromethane (500 ml) and washed twice with 2N aqueous hydrochloricacid (2×400 ml). The dichloromethane layer was dried over magnesiumsulphate, filtered and concentrated in vacuo. The resulting oil wassubjected to chromatography (SiO₂: 100% CH₂Cl₂) to yield thetoluenesulphonyl derivative of the amine as a white solid (7.59 g);

[0565] NMR Spectrum (CDCl₃) 2.42 (s, 3H), 2.73 (t, 2H, 3.21 (q, 2H),4.38 (t, 1H), 6.98 (t, 1H), 7.01 (s, 1H), 7.20 (d, 2H, 4-H and 6-H),7.30 and 7.69 (dd, 4H);

[0566] Mass Spectrum 310 (M+H)⁺;

[0567] Elemental Analysis Found Carbon 57.4%, hydrogen 5.29%, nitrogen4.40% (Calc. for C₁₅H₁₆ClNO₂0.25H₂O Carbon 57.3%, hydrogen 5.20%,nitrogen 4.46%).

[0568] ii) To a solution of the tosylated amine from i) above (5.0 g) inchloroform (50 ml) was added formaldehyde 37 wt. % solution in water(2.62 ml) followed by phosphoryl trichloride (40 ml). The reactionmixture was stirred under reflux for three hours. The reaction mixturewas cooled to room temperature then poured into a stirred mixture ofdichlorometharie (150 ml) and aqueous saturated sodium bicarbonatesolution (150 ml). Solid sodium bicarbonate was added portionwise withcaution until the aqueous layer became basic. The dichloromethane layerwas separated, washed with water (200 ml) then dried over magnesiumsulphate, filtered and concentrated in-vacuo. The crude product wassubjected to chromatography (SiO₂: 10-15% Ethyl acetate/iso-hexane) toyield 4-(6-chloro-1,2,3,4-tetrahydroisoquinolin-2-ylsulphonyl)toluene asa white crystalline solid which was recrystallised from ethylacetate/iso-hexane (2.26 g);

[0569] NMR Spectrum (CDCl₃, 250 MHz) 2.38 (s, 3H), 2.89 (t, 2H), 3.31(t, 2H), 4.17 (s, 2H), 6.95 (d, 1H), 7.06 (s, 1H), 7.12 (d, 1H), 7.31and 7.71 (dd, 4H);

[0570] Mass Spectrum 322 (M+H)⁺;

[0571] Elemental Analysis Found Carbon 60.0%, hydrogen 5.00%, nitrogen4.30% (Calc. for C₁₆H₁₆ClNO₂S Carbon 59.7%, hydrogen 5.01%, nitrogen4.35%).

[0572] iii) Part of the product from ii) above (2.20 g, 6.8 mmol) washeated at 75° C. with phenol (2.25 g) and 45% w/w hydrobromic acid inglacial acetic acid (30 ml) for three hours. The reaction mixture wascooled to room temperature then poured onto a mixture of ice anddichloromethane. The aqueous layer was adjusted to pH 14 with 6N sodiumhydroxide solution and extracted with dichloromethane (4×100 ml). Thedichloromethane layers were combined then dried over magnesium sulphate,filtered and concentrated in vacuo. The crude product was subjected tochromatography (SiO₂: 1-10% methanol/dichloromethane) to yield6-chloro-1,2,3,4-tetrahydroisoquinoline as a colourless oil (558.1 mg);

[0573] NMR Spectrum 2.66 (t, 2H), 2.88 (q, 2H), 3.78 (s, 2H), 6.98 to7.13 (m, 3H, Ar H's);

[0574] Mass Spectrum 168 (M+H)⁺.

EXAMPLE 40

[0575] To a solution of 5-methoxyindole-2-carboxylic acid (168 mg, 0.88mmol) in DMF (4 ml) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (168 mg,0.88 mmol), 1-hydroxybenzotriazole (118 mg, 0.88 mmol) and Et₃N (0.12ml, 0.88 mmol) followed by1-(4-pyridyl)-3-(5-amino-2-pyridyloxy)pyrrolidine (150 mg, 0.58 mmol)and the resulting suspension stirred at room temperature for 7 days. Themixture was poured into saturated aqueous NaHCO₃ solution and the solidprecipitate collected by filtration and washed with water then dried(over P₂O₅) to give1-(4-pyridyl)-(5-(6-methoxyindol-2-ylcarbonylamino)pyrid-2-yloxy)pyrrolidineas an off white solid (195 mg);

[0576] NMR Spectrum (CDCl₃) 2.20 (m, 2H), 3.50 (m, 4H), 3.80 (s, 3H),5.70 (m, 1H), 6.60 (m, 2H), 6.90 (m, 2H), 7.15 (s, 11H), 7.30 (m. 2H),8.10 (m, 3H), 8.60 (s, 11H).

[0577] MS (ESP+): m/e 430 (M+H)⁺.

[0578] The 1-(4-pyridyl)-3-(5-amino-2-pyridyloxy)pyrrolidine startingmaterial may be prepared as follows:

[0579] (a) Sodium hydride (60% dispersion in paraffin oil, 146 mg) 1.2equivalent) was added to an oven-dried round-bottomed flask and washedunder an argon atmosphere with pentane. DMF (5 ml) was then added,followed by 1-(4-pyridyl)-3-hydroxypyrrolidine (1.0 equivalent, 3.05mmol) and tetra-n-butylammonium bromide (59 mg, 0.18 mmol). The mixturewas added as a slurry to 2-bromo-5-nitropyridine (1.5 equivalent) in asecond dry flask under argon, with stirring. After the reaction wascomplete the solvent was evaporated under vacuum. The residue waspurified by chromatography on silica, eluting from 1%MeOH/1%NH₄OH/CH₂Cl₂to 10%MeOH/1%NH₄OH/CH₂Cl₂ (in 1% increments). The crude product wasrecrystallised from EtOAc to give1-(4-pyridyl)-3-(5-nitro-2-pyridyloxy)pyrrolidine as a pale brown solid(460 mg);

[0580] NMR Spectrum (CDCl₃): 2.4 (m, 2H), 3.58 (m, 3H), 3.8 (dd, 11H),5.85 (m, 1H), 6.4 (d, 2H), 6.82 (d, 1H), 8.22 (m, 2H), 8.38 (dd, 1H),9.08 (s. 1H). MS (ESP+): m/e 287 (M+H)⁺.

[0581] (b) A solution of1-(4-pyridyl)-3-(5-nitro-2-pyridyloxy)pyrrolidine (15.29 g, 53.46 mmol)in methanol (500 ml) was hydrogenated over 10% Pd/C at 5 bar for 18 h.The catalyst was removed by filtration and the solvent evaporated togive the product as a pale yellow solid (12.68 g).

[0582] NMR Spectrum (CDCl₃): 2.30 (m, 2H), 3.40 (m, 5H), 3.70 (dd, 1H),5.60 (m, 1H), 6.40 (d, 2H), 6.60 (d, 1H), 7.00 (m, 1H), 7.60 (s, 1H),8.10 (d, 2H). MS (ESP+): m/e 257 (M+H)⁺.

EXAMPLE 41

[0583] A mixture of 1-(2-methylpyrid-4-yl)piperazine dihydrochloride(145 mg), triethylamine (0.16 ml), N-hydroxysuccinimide ester from part(iv) of Example 26 (244 mg) and DMF (10 ml) was stirred for 16 hours.The solvent was evaporated and the residue dissolved in methylenechloride and washed with water. The aqueous washings were extracted withfurther methylene chloride and the combined organic extracts dried(MgSO₄) and evaporated. The residue was further purified by columnchromatography using a 9:1 mixture of methylene chloride and methanol aseluant and the resulting solid triturated under diethyl ether. There wasthus obtained1-[4-(6-bromonaphth-2-ylsulphonyl)-benzoyl]-4-(2-methylpyrid-4-yl)piperazine(115 mg);

[0584] NMR Spectrum (DMSO-d⁶+D₂O) 2.28 (s, 3H), 3.20-3.48 (m, 6H), 3.66(bs, 2H), 6.61 (d, 1H), 6.67 (s, 1H), 7.63 (d, 2H), 7.80 (d, 1H), 7.97(t, 2H), 8.06-8.17 (m, 4H), 8.32 (s, 1H), 8.72 (s, 1H);

[0585] Mass Spectrum m/z 550/552 (M+H);

[0586] Elemental Analysis Found C, 57.7; H 4.2; N, 7.7, S, 5.8;C₂₇H₂₄BrN₃O₃S 0.5H₂O requires: C, 58.0; H, 4.5; N, 7.5, S, 5.7%.

EXAMPLE 42

[0587] The ester from Example 26 (iv) above (488 mg) was treated with1-(4-pyridyl) hexahydro-1,4-diazepine (195 mg) in dimethylformamide (10ml) and stirred at ambient temperature for 18 hours. After removal ofthe solvent in vacuo and addition of ethyl acetate (30 ml), washing withsaturated sodium bicarbonate solution (30 ml), water (2×30 ml) and brine(30 ml), the reaction mixture was dried (MgSO4) and evaporated to awhite solid. Purification by column chromatography on silica gel,eluting with dichloromethane containing an increasing proportion ofmethanol (2-5%) and a small amount of conc. aqueous ammonia, followed byrecrystallisation from ethyl acatate gave as a solid1-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]-4-(4-pyridyl)hexahydro-1,4-diazepine(290 mg).

[0588] NMR Spectrum (CDCl₃) 2.0-2.2 (m, 2H); 3.3 (m, 1H); 3.4-3.5 (m,1H); 3.6-3.8 (bm, 5H); 4.0 (m, 1H); 6.7 (d, 2H); 7.05 (m, 1H); 7.4 (dd,1H); 7.7 (m, 1H); 7.9 (m, 3H); 8.0 (m, 2H); 8.1 (m, 1H); 8.15-8.5 (m,2H); 8.55 (s, 1H).

[0589] Mass Spectrum m/z 550/552 m+H.

[0590] Elemental Analysis Found C: 58.8; H: 4.6; N: 7.1; S: 5.2%.C₂₇H₂₄BrN₃O₃S Requires C: 58.6; H: 4.7; N: 7.1; S: 5.4%.

[0591] The 1-(4-pyridyl)hexahydro-1,4-diazepine used as startingmaterial may be prepared as follows:

[0592] A suspension of 4-chloropyridine hydrochloride (7.5 g) in3-methyl-1-butanol (100 ml) was added dropwise to a refluxing solutionof hexahydro-1,4-diazepine (10.0 g) and triethylamine (16.8 ml) in3-methyl-1-butanol (300 ml). After addition the solution was refluxedfor 18 hours. The solvent was removed in vacuo to give an oil.Purification by sinter-column chromatography on silica gel, eluting withdichloromethane containing an increasing proportion of methanol (2-5%)and a small amount of conc. aqueous ammonia, gave1-(4-pyridyl)hexahydro-1,4-diazepine as a colourless oil which slowlycrystallised on standing.

[0593] NMR Spectrum (CDCl₃) 1.8-2.1 (m, 2H); 2.8 (m, 2H); 3.0 (m, 2H);3.4-3.7 (m, 5H); 6.5 (d, 2H); 8.2 (d, 2H).

[0594] Mass Spectrum m/z 178 m+H.

EXAMPLE 43

[0595] The following illustrate representative pharmaceutical dosageforms containing the compound of formula I, or apharmaceutically-acceptable salt thereof (hereafter compound X), fortherapeutic or prophylactic use in humans: (a) Tablet I mg/tabletCompound X 100 Lactose Ph. Eur 182.75 Croscarmellose sodium 12.0 Maizestarch paste (5% w/v paste) 2.25 Magnesium stearate 3.0

[0596] (b) Tablet II mg/tablet Compound X 50 Lactose Ph. Eur 223.75Croscarmellose sodium 6.0 Maize starch 15.0 Polyvinylpyrrolidone (5% w/vpaste) 2.25 Magnesium stearate 3.0

[0597] (c) Tablet III mg/tablet Compound X 1.0 Lactose Ph. Eur 93.25Croscarmellose sodium 4.0 Maize starch paste (5% w/v paste) 0.75Magnesium stearate 1.0

[0598] (d) Capsule mg/capsule Compound X 10 Lactose Ph. Eur 488.5Magnesium stearate 1.5

[0599] (e) Injection I (5.0 mg/ml) Compound X 5.0% w/v 1M Sodiumhydroxide solution 15.0% v/v 0.1M Hydrochloric acid (to adjust pH to7.6) Polyethylene glycol 400 4.5% w/v Water for injection to 100%

[0600] (f) Injection II 10 mg/ml) Compound X 1.0% w/v Sodium phosphateBP 3.6% w/v 0.1M Sodium hydroxide solution 15.0% v/v Water for injectionto 100%

[0601] (g) Injection III (1 mg/ml, buffered to pH6) Compound X 0.1% w/vSodium phosphate BP 2.26% w/v Citric acid 0.38% w/v Polyethylene glycol400 3.5% w/v Water for injection to 100%

[0602] Note

[0603] The above formulations may be obtained by conventional procedureswell known in the pharmaceutical art. The tablets (a)-(c) may be entericcoated by conventional means, for example to provide a coating ofcellulose acetate phthalate.

1. An aminoheterocyclic derivative of the formula I

wherein G¹ is CH or N; G² is CH or N; m is 1 or 2; R¹ is hydrogen,halogeno, trifluoromethyl, trifluoromethoxy, cyano, amino, hydroxy,nitro, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino ordi-(1-4C)alkylamino; L¹ is (1-4C)alkylene, (3-6C)cycloalkane-1,2-diyl or(1-3C)alkylene-carbonyl, T¹ is CH or N, R² is hydrogen or (1-4C)alkyland R³ is hydrogen or (1-4C)alkyl, or R² and R³ together form a(1-4C)alkylene or methylenecarbonyl group, and wherein 1 or 2 methylenegroups within L¹ or the ring formed when R² and R³ are linked optionallybear 1 or 2 substituents selected from carboxy, carbanoyl, (1-4C)alkyl,(1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl,N,N-di-(1-4C)alkylcarbamoyl, pyrrolidin-1-ylcarbonyl,piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl,4-(1-4C)alkylpiperazin-1-ylcarbonyl, hydroxy-(1-4C)alkyl,(1-4C)alkoxy-(1-4C)alkyl, carboxy-(1-4C)alkyl,(1-4C)alkoxycarbonyl-(1-4C)alkyl, carbamoyl-(1-4C)alkyl, N-(1C)alkylcarbamoyl-(1-4C)alkyl, N,N-di-(1-4C)alkylcarbamoyl-(1-4C)alkyl,pyrrolidin-1-ylcarbonyl-(1-4C)alkyl, piperidino-(l 14C)alkyl,morpholino-(1-4C)alkyl, piperazin-1-yl-(1-4C)alkyl and4-(1-4C)alkylpiperazin-1-yl-(1-4C)alkyl, and wherein any heterocyclicgroup in said substituent optionally bears 1 or 2 (1-4C)alkylsubstituents, provided that, when T¹ is N, L¹ is not optionallysubstituted methylene and R² and R³ together do not form an optionallysubstituted methylene group; X¹ is a group of the formula SO, SO₂,C(R⁴)₂, CO, C(R⁴)₂O, C(R⁴)₂S, C(R⁴)₂SO, C(R⁴)₂SO₂, COC(R⁴)₂, SOC(R⁴)₂ orSO₂C(R⁴)₂ when T¹ is CH or N, or, in addition, X¹ is a group of theformula O, S, OC(R⁴)₂ or SC(R⁴)₂ when T¹ is CH, and wherein each R⁴ isindependently hydrogen or (1-4C)alkyl; Ar is phenylene, or a 5- or6-membered monocyclic heteroaryl ring containing up to 3 heteroatomsselected from nitrogen, oxygen and sulphur, and wherein said phenyleneor heteroaryl ring is optionally substituted with 1 or 2 substituentsselected from halogeno, trifluoromethyl, trifluoromethoxy, cyano, nitro,(1-4C)alkyl, (2-4C)alkenyl and (2-4C)alkynyl, from the substituent Y¹which is selected from hydroxy, amino, (1-4C)alkoxy, (2-4C)alkenyloxy,(2-4C)alkynyloxy, (1-4C)alkylamino, di-(1-4C)alkylamino,pyrrolidin-1-yl, piperidino, morpholino, thiamorpholino,1-oxothiamorpholino, 1,1-dioxothiamorpholino, piperazin-1-yl,4-(1-4C)alkylpiperazin-1-yl, (1-4C)alkylthio, (1-4C)alkylsulphinyl,(1AC)alkylsulphonyl, (2-4C)alkanoylamino, benzamido,(1-4C)alkanesulphonamido and benzenesulphonamido, from the substituentY² which is selected from carboxy, carbamoyl, (1-4C)alkoxycarbonyl,N-(1-4C)alkylcarbamoyl, N,N-di-(1-4C)alkylcarbamoyl,pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl,thiamorpholinocarbonyl, 1-oxothiamorpholinocarbonyl,1,1-dioxothiamorpholinocarbonyl, piperazin-1-ylcarbonyl,4-(1-4C)alkylpiperazin-1-ylcarbonyl, (1-4C)alkanesulphonamidocarbonyl,benzenesulphonamidocarbonyl and benzylsulphonamidocarbonyl, from asubstituent of the formula -L²-Y¹ wherein L² is (1-4C)alkylene and Y¹has any of the meanings defined immediately hereinbefore, from asubstituent of the formula -L²-Y² wherein L² is (1-4C)alkylene and Y²has any of the meanings defined immediately hereinbefore, from asubstituent of the formula —X³-L²-Y² wherein X³ is a group of theformula CON(R⁵), CON(L²-Y²), C(R⁵)₂O, O, N(R⁵) or N(L²-Y²), L² is(1-4C)alkylene, Y² has any of the meanings defined immediatelyhereinbefore and each R⁵ is independently hydrogen or (1-4C)alkyl, andfrom a substituent of the formula —X³-L³-Y¹ wherein X³ is a group of theformula CON(R⁵), CON(L³-Y¹), C(R⁵)₂O, O, N(R⁵) or N(L³-Y¹), L³ is(2-4C)alkylene, Y¹ has any of the meanings defined immediatelyhereinbefore and each R⁵ is independently hydrogen or (1-4C)alkyl, andwherein any heterocyclic group in said substituent optionally bears 1 or2 substituents selected from carboxy, carbamoyl, (1-4C)alkyl,(1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl andN,N-di-(1-4C)alkylcarbamoyl, and wherein any phenyl group in saidsubstituent optionally bears 1 or 2 substituents selected from halogeno,trifluoromethyl, cyano, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl,(1-4C)alkoxy, (2-4C)alkenyloxy and (2-4C)alkynyloxy; X² is a group ofthe formula S, SO, SO₂, C(R⁶)₂, CO, N(R⁷)SO₂, N(R⁷)CO, C(R⁶)₂S,C(R⁶)₂SO, C(R⁶)₂SO₂, C(R⁶)₂—C(R⁶)₂ or C(R⁶)₂CO, or, in addition, X² is agroup of the formula O, SO₂N(R⁷), CON(R⁷) or C(R⁶)₂O when Q is otherthan phenyl-(2-4C)alkenyl or phenyl-(2-4C)alkynyl and wherein each R⁶ isindependently hydrogen or (1-4C)alkyl and R⁷ is hydrogen, (1-4C)alkyl ora group of the formula —X⁴-Q wherein X⁴ is SO₂ or CO and Q has any ofthe meanings defined immediately hereinafter; and Q is phenyl, naphthyl,phenyl-(1-4C)alkyl, phenyl-(2-4C)alkenyl, phenyl-(2-4C)alkynyl or aheterocyclic moiety containing up to 4 heteroatoms selected fromnitrogen, oxygen and sulphur, and Q optionally bears 1, 2 or 3substituents selected from halogeno, trifluoromethyl, trifluoromethoxy,cyano, hydroxy, amino, nitro, trifluoromethanesulphonyl, carboxy,carbamoyl, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy,(2-4C)alkenyloxy, (2-4C)alkynyloxy, (1-4C)alkylthio,(1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, (1-4C)alkylamino,di-(1-4C)alkylamino, (1-4C)alkoxycarbonyl, (1-4C)alkylcarbamoyl,N,N-di-(1-4C)alkylcarbamoyl, (2-4C)alkanoyl, (2-4C)alkanoylamino,hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, carboxy-(1-4C)alkyl,(1-4C)alkoxycarbonyl-(1-4C)alkyl, carbamoyl-(1-4C)alkyl,N-(1-4C)alkylcarbamoyl-(1-4C)alkyl,N,N-di-(1-4C)alkylcarbamoyl-(1-4C)alkyl, phenyl, heteroaryl, phenoxy,phenylthio, phenylsulphinyl, phenylsulphonyl, benzyl, benzoyl,heteroaryloxy, heteroarylthio, heteroarylsulphinyl andheteroarylsulphonyl, and wherein said heteroaryl substituent or theheteroaryl group in a heteroaryl-containing substituent comprises a 5-or 6-membered monocyclic heteroaryl ring containing up to 3 heteroatomsselected from nitrogen, oxygen and sulphur, and wherein said phenyl,heteroaryl, phenoxy, phenylthio, phenylsulphinyl, phenylsulphonyl,heteroaryloxy, heteroarylthio, heteroarylsulphinyl, heteroarylsulphonyl,benzyl or benzoyl substituent optionally bears 1, 2 or 3 substituentsselected from halogeno, trifluoromethyl, cyano, hydroxy, amino, nitro,carboxy, carbamoyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino,di-(1-4C)alkylamino, (1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl,N,N-di-(1-4C)alkylcarbamoyl and (2-4C)alkanoylamino; or apharmaceutically-acceptable salt thereof, provided that when X¹ is COand Ar is phenylene which optionally bears 1 or 2 substituents selectedfrom halogeno, trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy then X² isnot N(R⁷)SO₂, N(R⁷)CO, C(R⁶)₂S, C(R⁶)₂SO, C(R⁶)₂SO₂, C(R⁶)₂—C(R⁶)_(2,)C(R⁶)₂CO or C(R⁶)₂O.
 2. A compound according to claim 1 wherein: each ofG¹ and G² is CH; or G¹ is CH and G² is N, or G¹ is N and G² is CH; m is1 and R¹ is hydrogen; L¹ is (1-4C)alkylene, T¹ is CH or N, and R¹ and R³together form a (1-4C)alkylene group, and wherein 1 or 2 methylenegroups within L¹ and the ring formed when R² and R³ are linkedoptionally bears 1 or 2 (1-4C)alkyl substituents, provided that, when T¹is N, L¹ is not optionally substituted methylene and R² and R³ togetherdo not form an optionally substituted methylene group; when T¹ is CH orN, X¹ is a group of the formula SO₂, CH₂, CO, CH₂O, CH₂S, CH₂SO₂, COCH₂or SO₂CH₂, or, when T¹ is CH, X¹ is, in addition, a group of the formulaO, S, OCH₂ or SCH₂; Ar is 1,3-phenylene or 1,4-phenylene which isoptionally substituted with 1 or 2 substituents selected from halogeno,trifluoromethyl, cyano, (1-4C)alkyl, hydroxy, amino, (1-4C)alkoxy,(1-4C)alkylamino, di-(1-4C)alkylamino, (1-4C)alkylthio,(1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, (2-4C)alkanoylamino,carboxy, carbamoyl, (1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl,N,N-di-(1-4C)alkylcarbamoyl, pyrrolidin-1-ylcarbonyl,piperidinocarbonyl, morpholinocarbonyl, thiamorpholinocarbonyl,1-oxothiamorpholinocarbonyl, 1,1-dioxothiamorpholinocarbonyl,piperazin-1-ylcarbonyl and 4-(1-4C)alkylpiperazin-1-ylcarbonyl; or Ar is1,3-phenylene or 1,4-phenylene which is optionally substituted with asubstituent of the formula -L²-Y¹ or of the formula, -L²-Y² wherein L²is (1-4C)alkylene, Y¹ is selected from hydroxy, amino, (1-4C)alkoxy,(1-4C)alkylamino, di-(1-4C)alkylamino, pyrrolidin-1-yl, piperidino,morpholino, piperazin-1-yl, 4-(1-4C)alkylpiperazin-1-yl,(1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl and(2-4C)alkanoylamino, and Y² is selected from carboxy, carbamoyl,(1-4C)alkoxycarbonyl, L-(1-4C)alkylcarbamoyl,N,N-di-(1-4C)alkylcarbamoyl, pyrrolidin-1-ylcarbonyl,piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl and4-(1-4C)alkylpiperazin-1-ylcarbonyl; or Ar is 1,3-phenylene or1,4-phenylene which is optionally substituted with a substituent of theformula —X³-L²-Y² wherein X³ is a group of the formula CONH, CON(Me),CH₂O or O, L² is methylene, ethylene or trimethylene and Y² is selectedfrom carboxy, carbamoyl, (1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl,N,N-di-(1-4C)alkylcarbamoyl, pyrrolidin-1-ylcarbonyl,piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl and4-(1-4C)alkylpiperazin-1-yl; or Ar is 1,3-phenylene or 1,4-phenylenewhich is optionally substituted with a substituent of the formula—X³-L³-Y¹ wherein X³ is a group of the formula CONH, CH₂O, O or NH, L³is ethylene or trimethylene and Y¹ is hydroxy, amino, (1-4C)alkoxy,(1-4C)alkylamino, di-(1-4C)alkylamino, pyrrolidin-1-yl, piperidino,morpholino, piperazin-1-yl, 4-(1-4C)alkylpiperazin-1-yl,(1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl and(2-4C)alkanoylamino; X² is a group of the formula SO₂, CH₂, CO, NHSO₂,N(R⁷)SO₂, NHCO, N(R⁷)CO, CH₂SO₂, CH₂CH₂ or CH₂CO wherein R⁷ is(1-4C)alkyl or a group of the formula —X₄-Q wherein X⁴ is SO₂ and Q hasany of the meanings defined hereinafter in this section of particularcompounds of the invention; or X² is a group of the formula S; Q isphenyl, naphthyl or phenyl-(1-4C)alkyl which optionally bears 1, 2 or 3substituents selected from hydroxy, halogeno, cyano, trifluoromethyl,(1-4C)alkyl, (1-4C)alkoxy, phenyl, phenoxy, phenylthio, phenylsulphinyl,phenylsulphonyl, benzyl and benzoyl, and wherein the phenyl substituentor the phenyl group in a phenyl-containing substituent optionally bears1 or 2 substituents selected from halogeno, (1A-4C)alkyl and(1-4C)alkoxy; or Q is phenyl-(2-4C)alkenyl or phenyl-(2-4C)alkynyl whichoptionally bears 1, 2 or 3 substituents selected from halogeno, cyano,trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy; or Q is phenyl orphenyl-(1-4C)alkyl which bears 1 substituent selected from heteroaryl,heteroaryloxy, heteroarylthio, heteroarylsulphinyl andheteroarylsulphonyl, wherein the heteroaryl substituent or theheteroaryl group in a heteroaryl-containing substituent comprises a 5-or 6-membered monocyclic heteroaryl ring containing up to 3 heteroatomsselected from nitrogen, oxygen and sulphur, and wherein said heteroarylor heteroaryl-containing substituent optionally bears 1 or 2substituents selected from halogeno, (1-4C)alkyl and (1-4C)alkoxy; or Qis a heterocyclic moiety containing up to 2 heteroatoms selected frombenzofuranyl, quinolyl, tetrahydroquinolyl, isoquinolyl, quinoxalinyl,quinazolinyl, cinnolinyl, indolyl, benzimidazolyl, indazolyl,benzoxazolyl, benzothiazolyl, dibenzofuranyl and dibenzothienyl, and Qoptionally bears 1 or 2 substituents selected from halogeno, cyano,trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy; or Q is a heterocyclicmoiety containing up to 4 heteroatoms selected from furyl, thienyl,pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, oxadiazolyl, thiadiazolyl and tetrazolyl, and Qoptionally bears 1 or 2 substituents selected from halogeno, cyano,carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy,N-(1-4C)alkylcarbamoyl and N,N-di-(1-4C)alkylcarbamoyl; or Q is aheterocyclic moiety containing up to 2 heteroatoms selected fromthienyl, pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, oxazolyl andthiazolyl, and Q optionally bears 1 or 2 substituents selected fromphenyl, heteroaryl, phenoxy, phenylthio, phenylsulphinyl,phenylsulphonyl, heteroaryloxy, heteroarylthio, heteroarylsulphinyl,heteroarylsulphonyl, benzyl and benzoyl, wherein the heteroarylsubstituent or the heteroaryl group in a heteroaryl-containingsubstituent is selected from thienyl, pyridyl, pyrimidinyl, pyrazolyl,oxazolyl and thiazolyl, and wherein said phenyl, phenyl-containing,heteroaryl or heteroaryl-containing substituent optionally bears 1 or 2substituents selected from halogeno, (I 4C)alkyl and (1-4C)alkoxy; or apharmaceutically-acceptable salt thereof; provided that when X¹ is COand Ar is phenylene which optionally bears 1 or 2 substituents selectedfrom halogeno, trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy then X² isnot N(R⁷)SO₂, N(R⁷)CO, C(R⁶)₂S, C(R⁶)₂SO, C(R⁶)₂SO₂, C(R⁶)₂—C(R⁶)₂,C(R⁶)₂CO or C(R⁶)₂O.
 3. A compound according to claim 1 or 2 whereineach of G¹ and G² is CH, G¹ is CH and G² is N, or G¹ is N and G² is CH;m is 1 and R¹ is hydrogen; L¹ is ethylene, T¹ is CH or N, and R² and R³are independently hydrogen or together form an ethylene group; when T¹is CH or N. X¹ is a group of the formula CH₂, CO, CH₂O or SO₂, or, whenT, is CH, X¹ is, in addition, a group of the formula O; Ar is1,2-phenylene, 1,3-phenylene or 1,4-phenylene which is optionallysubstituted with 1 or 2 substituents selected from fluoro, chloro,bromo, trifluoromethyl, cyano, methyl, hydroxy, amino, methoxy,methylamino, dimethylamino, methylthio, methylsulphinyl,methylsulphonyl, acetamido, carboxy, carbamoyl, methoxycarbonyl,ethoxycarbonyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl,2-(ethylthio)ethylaminocarbonyl, pyrrolidin-1-ylcarbonyl,piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl and4-methylpiperazin-1-ylcarbonyl; X² is a group of the formula S, SO₂,CONH, NHSO₂ or N(R⁷)SO₂ wherein R⁷ is methyl or a group of the formula—SO₂Q wherein Q has any of the meanings defined immediately hereinafter;and Q is phenyl, styryl, 1,4-tetrahydroisoquinolinyl, 4-biphenylyl or2-naphthyl which optionally bears 1 or 2 substituents selected fromfluoro, chloro, bromo, trifluoromethyl, 4-chlorophenoxy, methyl andmethoxy; or a pharmaceutically-acceptable salt thereof; provided thatwhen X¹ is CO and Ar is 1,2-, 1,3- or 1,4-phenylene which optionallybears 1 or 2 substituents selected from fluoro, chloro, bromo,trifluoromethyl, methyl and methoxy then X² is not NHSO₂ or N(R⁷)SO₂wherein R⁷ is methyl or a group of the formula —SO₂-Q wherein Q has anyof the meanings defined immediately hereinbefore.
 4. A compoundaccording to any one of claims 1 to 3 wherein each of G¹ and G² is CH,G¹ is CH and G² is N, or G¹ is N and G² is CH; m is 1 and R¹ ishydrogen; L¹ is ethylene, T¹ is CH or N, and R² and R³ together form anethylene group; when T¹ is CH or N, X¹ is a group of the formula CH₂, COor CH₂O, or, when T¹ is CH, X¹ is, in addition, a group of the formulaO; Ar is 1,3-phenylene or 1,4-phenylene which is optionally substitutedwith 1 or 2 substituents selected from fluoro, chloro, bromo,trifluoromethyl, cyano, methyl, hydroxy, amino, methoxy, methylamino,dimethylamino, methylthio, methylsulphinyl, methylsulphonyl, acetamido,carboxy, carbamoyl, methoxycarbonyl, ethoxycarbonyl, N-methylcarbamoyl,N,-dimethylcarbamoyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl,morpholinocarbonyl, piperazin-1-ylcarbonyl and4-methylpiperazin-1-ylcarbonyl; X² is a group of the formula SO₂, NHSO₂or N(R⁷)SO₂ wherein R⁷ is methyl or a group of the formula —SO₂Q whereinQ has any of the meanings defined immediately hereinafter; and Q isphenyl, styryl, 4-biphenylyl or 2-naphthyl which optionally bears 1 or 2substituents selected from fluoro, chloro, bromo, trifluoromethyl,methyl and methoxy; or a pharmaceutically-acceptable salt thereof;provided that when X¹ is CO and Ar is 1,3- or 1,4-phenylene whichoptionally bears 1 or 2 substituents selected from fluoro, chloro,bromo, trifluoromethyl, methyl and methoxy then X² is not NHSO₂ orN(R⁷)SO₂ wherein R⁷ is methyl or a group of the formula —SO₂-Q wherein Qhas any of the meanings defined immediately hereinbefore.
 5. A compoundaccording to any one of claims 1 to 4 wherein each of G¹ and G² is CH,G¹ is CH; and G² is N, or G¹ is N and G² is CH; m is 1 and R¹ ishydrogen; L¹ is ethylene, T¹ is N, and R² and R³ together form anethylene group; X¹ is a group of the formula CO; Ar is 1,4-phenylene,2-carboxy-1,4-phenylene or 2-piperidinocarbonyl-1,4-phenylene (with theX¹ group in the 1-position and the X² group in the 4-position); X² is agroup of the formula SO₂; and Q is 2-naphthyl, styryl or 4-biphenylylwhich optionally bears 1 or 2 substituents selected from fluoro, chloroand bromo; or a pharmaceutically-acceptable salt thereof.
 6. A compoundaccording to any one of claims 1 to
 5. wherein each of G¹ and G² is CH;m is 1 and R¹ is hydrogen; L¹ is ethylene. T¹ is N, and R² and R³together form an ethylene group; X¹ is a group of the formula CO; Ar is1,4-phenylene, 2-carboxy-1,4-phenylene or2-piperidinocarbonyl-1,4-phenylene (with the X¹ group in the 1-positionand the X² group in the 4-position); X² is a group of the formula SO₂;and Q is 2-naphthyl, styryl or 4-biphenylyl which optionally bears 1 or2 substituents selected from fluoro, chloro and bromo; or apharmaceutically-acceptable salt thereof.
 7. A compound according to anyone of claims, 1 to 6 which is:1-[4-(6-chloronaphth-2-ylsulphonyl)benzoyl]-4-(4-pyridyl)piperazine,1-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]-4-(4-pyridyl)piperazine,1-[4-(2-naphthylsulphonyl)benzoyl]-4-(4-pyridyl)piperazine,1-{4-[(E)-4-chlorostyrylsulphonyl]benzoyl}-4-(4-pyridyl)piperazine,1-[4-(4′-bromo-4-biphenylylsulphonyl)benzoyl]-4-(4-pyridyl)piperazine,1-[4-(4′-chloro-4-biphenylylsulphonyl)benzoyl]-4-(4-pyridyl)piperazine,1-[4-(4-biphenylylsulphonyl)benzoyl]-4-(4-pyridyl)piperazine,5-(6-chloronaphth-2-ylsulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylcarbonyl]benzoicacid,5-(2-naphthylsulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylcarbonyl]benzoicacid,5-(4′-bromo-4-biphenylylsulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylcarbonyl]benzoicacid,5-[(E)-4-chlorostyrylsulphonyl]-2-[4-(4-pyridyl)piperazin-1-ylcarbonyl]benzoicacid,1-{5-(6-bromonaphth-2-ylsulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylcarbonyl]benzoyl}-piperidine,1-{5-(6-chloronaphth-2-ylsulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylcarbonyl]benzoyl}-piperidine,1-{5-(4′-bromo-4-biphenylylsulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylcarbonyl]benzoyl}-piperidine,1-{5-[(E)-4-chlorostyrylsulphonyl]-2-[4-(4-pyridyl)piperazin-ylcarbonyl]benzoyl}piperidine,4′-bromo-N-{4-[1-(4-pyridyl)piperidin;-4-yloxy]phenyl}4-biphenylylsulphonamide,4-chloro-N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-(E)-styrylsulphonamide,6-bromo-N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-2-naphthalenesulphonamide,N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-4-toluenesulphonamide,N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-N-(4-tolylsulphonyl)-4-toluenesulphonamide,4-chloro-N-methyl-N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-(E)-styrylsulphonamide,4′-bromo-N-methyl-N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-4-biphenylylsulphonamide,4′-bromo-N-(4-[1-(4-pyridyl)piperidin-4-ylmethoxy]phenyl)}4-biphenylylsulphonamide,6-bromo-N-{4-[1-(4-pyridyl)piperidin-4-ylmethoxy]-phenyl}-2-naphthalenesulphonamide,4-chloro-N-{4-[1-(4-pyridyl)piperidin-4-ylmethoxy]phenyl}-(E)-styrylsulphonamide,4′-bromo-N-(4′-bromo-4-biphenylylsulphonyl)-N-{4-[1-(4-pyridyl)piperidin-4-ylmethoxy]phenyl}4-biphenylylsulphonamide,6-bromo-N-(6-bromonaphth-2-ylsulphonyl)-N-{4-[1-(4-pyridyl)piperidin-4-ylmethoxy]phenyl}-2-naphthalenesulphonamide,6-bromo-N-{3-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-2-naphthalenesulphonamide,4-[4-chlorophenylsulphonyl)phenoxy]-1-(4-(pyridyl)piperidine,5-(6-bromonaphth-2-ylsulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylcarbonyl]benzoicacid,4-(6-bromonaphth-2-ylsulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylcarbonyl]benzoicacid,1-[4-(4-(4-chlorophenoxy)phenylaminocarbonyl)benzyl]-4-(4-pyridyl)piperazine,6-bromo-N-{2-[1-(4-pyridyl)piperidin-4-ylmethoxy]phenyl}-2-naphthalenesulphonamide,4-chloro-N-{3-[1-(4-pyridyl)piperidin-4yloxy]phenyl}-(E)-styrylsulphonamide,4-[4-(6-bromonaphth-2-ylsulphonyl)phenoxy]-1-(4-pyridyl)piperidine,4-[4-(6-bromonaphth-2-ylsulphonyl)bcnzoyl]-1-(4-pyridyl)piperidine,4-[4-(6-bromonaphth-2-ylthio)benzoyl]-1-(4-pyridyl)piperidine,1-[4-(6-bromonaphth-2-ylsulphonyl)phenylsulphonyl]-1-(4-pyridyl)piperazine,6-(bromo-2-(4-(2-pyrimidin-4-yl)aminoethylaminocarbonyl)phenylsulphonyl)naphthalene,1-[4-(6-bromonaphth-2-ylthio)benzoyl]-4-(4-pyridyl)piperazine,1-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]-4-(4-pyridyl)piperazine,1-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]-4-(4-pyrimidinyl)-piperazine,1-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]-4-(4-pyridazinyl)piperazine,1-[4-(6-bromonaphth-2-ylsulphonyl-2-trifluoromethylbenzoyl]-4-(4-pyridyl)piperazine,1-[4-(6-bromonaphth-2-ylthio)-2-trifluoromethylbenzoyl]-4-(4-pyridyl)piperazine,1-[4-(6-bromonaphth-2-ylthio)-2-carboxybenzoyl]-4-(4-pyridyl)piperazine1-[5-(6-bromonaphth-2-ylthio)-2-carboxybenzoyl]-4-(4-pyridyl)piperazine,1-[5-(6-bromonaphth-2-ylsulphonyl)-2-methoxycarbonylbenzoyl]-4-(4-pyridyl)piperazine,1-[4-(6-bromonaphth-2-ylsulphonyl)-2-methoxycarbonylbenzoyl]44-pyridyl)piperazine,1-[4-(6-bromonaphth-2-ylsulphonyl)-2-(2-(ethylthio)-ethylaminocarbonyl)benzoyl]4(4-pyridyl)piperazine,1-[5-(6-bromonaphth-2-yisulphonyl)-2-(2-ethylthio)ethylaminocarbonyl)benzoyl]-4-(4-pyridyl)piperazine,1-[4-(6-bromonaphth-2-ylsulphonyl)-2-(piperidin-1-ylcarbonyl]-4-(4-pyridyl)piperazine,1-[5-(6-bromonaphth-2-ylsulphonyl)-2-(piperidin-1-ylcarbonyl]-4-(4-pyridyl)piperazine,1-[4-(4-(3-chlorophenyl)piperazin-1-ylsulphonyl)benzoyl]-4-(4-pyridyl)piperazine,1-[4-(6-chloro-1,2,3,4-tetrahydroisoquinolin-2-ylsulphonylbenzoyl]-4-(4-pyridyl)piperazine,1-(4-pyridyl)-(5-(6-methoxyindol-2-ylcarbonylamino)pyrid-2-yloxy)pyrrolidine,1-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]-4-(2-methylpyrid-4-yl)piperazine,1-[4-(6-bromonaphth-2-ylsulphonyl)benzoyl]-4-(4-pyridyl)hexahydro-1,4-diazepine, or a pharmaceutically-acceptable salt thereof.
 8. Aprocess for the preparation of an aminoheterocyclic derivative of theformula I or a pharmaceutically acceptable salt thereof as claimed asclaim 1 which comprises: a) for the production of those compounds of theformula I wherein T¹ is N and X¹ is CO, the reaction, conveniently inthe presence of a suitable base, of an amine of the formula II

 with an acid of the formula III HO₂C—Ar—X²-Q  III  or a reactivederivative thereof; (aa) for the preparation of those compounds of theformula I wherein T¹ is N and X¹ is a group of the formula COC(R⁴)₂, thereaction, conveniently in the presence of a suitable base, of an amineof the formula II with an acid of the formula: HO₂C—C(R⁴)₂—Ar—X²-Q  or areactive derivative thereof; (b) for the production of those compoundsof the formula I wherein T¹ is CH and X¹ is O or C(R⁴)₂O, the reaction,conveniently in the presence of a suitable coupling agent, of a compoundof the formula IV

 wherein n is 0 or 1 and Z is a displaceable group, with a phenoliccompound of the formula V HO—Ar—X²-Q  V (bb) for the preparation ofthose compounds of the formula I wherein T¹ is CH and X¹ is a group ofthe formula S or C(R⁴)₂S, the reaction, conveniently in the presence ofa suitable coupling agent, of a compound of the formula IV with acompound of the formula: HS—Ar—X₂-Q; (c) for the production of thosecompounds of the formula I wherein T¹ is N and X¹ is CH(R⁴), thereductive amination of a keto compound of the formula VIR⁴—CO—Ar—X²-Q  VI  with an amine of the formula VII

(d) for the production of those compounds of the formula I wherein X² isa group of the formula N(R⁷)SO₂, the reaction, conveniently in thepresence of a suitable base, of an amine of the formula VIII

 with a compound of the formula IX Z-SO₂-Q  IX  wherein Z is adisplaceable group; (dd) for the production of those compounds of theformula I wherein X² is a group of the formula N(R⁷)CO, the reaction,conveniently in the presence of a suitable base, of an amine of theformula VIII with a compound of the formula: Z-CO-Q; (e) for theproduction of those compounds of the formula I wherein X² is a group ofthe formula N(R)SO₂, the reaction, conveniently in the presence of asuitable base, of a sulphonamide of the formula X

 with a compound of the formula XI R⁵-Z  XI  wherein Z is a displaceablegroup; (ee) for the production of those compounds of the formula Iwherein X² is a group of the formula N(R⁷)CO, the reaction convenientlyin the presence of a suitable base, of a compound of the formula Iwherein N(R⁷)CO is NHCO with a compound of the formula XI; (f) for theproduction of those compounds of the formula I wherein X² is a group ofthe formula SO₂N(R⁷) the reaction, conveniently in the presence of asuitable base of a compound of the formula XII

 wherein Z is a displaceable group as defined hereinbefore, with anamine of the formula XIII (R⁷)NH-Q  XIII (ff) for the preparation ofthose compounds of the formula I wherein X² is a group of the formulaCON(R⁷), the reaction, conveniently in the presence of a suitable base,of a compound of the formula XIII with a carbonyl compound correspondingto the sulphonyl compound of the formula XII; (g) for the production ofthose compounds of the formula I wherein T¹ is CH and X¹ is a group ofthe formula OC(R⁴)₂, the reaction conveniently in the presence of asuitable coupling agent of an alcohol of the formula XIV

 with a compound of the formula XV Z-C(R⁴)₂—Ar—X²-Q  XV  wherein Z is adisplaceable group; (gg) for the preparation of those compounds of theformula I wherein T¹ is CH and X¹ is a group of the formula SC(R⁴)₂ thereaction conveniently in the presence of a suitable coupling agent ofthe thiol equivalent of formula XIV with a compound of the formula XV;(h) for the production of those compounds of the formula I wherein X² isa group of the formula C(R⁶)₂S, the reaction, conveniently in thepresence of a suitable base, of a compound of the formula XVI

 wherein Z is a displaceable group with a thiol of the formula XVIIHS-Q  XVII (i) for the production of those compounds of the formula Iwherein L¹, R², R³, Ar or Q bears a carboxy or carboxy-containing group,the hydrolysis of a compound of the formula I wherein L¹, R², R³, Ar orQ bears a (1-4C)alkoxycarbonyl group; (j) for the production of thosecompounds of the formula I wherein L¹, R², R³, Ar or Q bears acarbamoyl, N-alkylcarbamoyl or N,N-dialkylcarbamoyl group, the reactionof a compound of the formula I wherein L¹, R², R³, Ar or Q bears acarboxy group, or a reactive derivative thereof as defined hereinbefore,with ammonia or an appropriate alkylamine or dialkylamine; (k) for theproduction of those compounds of the formula I wherein X¹ is a group ofthe formula SO, SO₂, C(R⁴)₂SO, C(R⁴)₂SO₂, SOC(R⁴)₂ or SO₂C(R⁴)₂, whereinAr bears a (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl,1-oxothiamorpholino or 1,1-dioxothiamorpholino group or a substituentwhich contains a (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl,1-oxothiamorpholino or 1,1-dioxothiamorpholino group, wherein X² is agroup of the formula SO, SO₂, C(R⁶)₂SO or C(R⁶)₂SO₂, or wherein Q bearsa (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, phenylsulphinyl,phenylsulphonyl, heteroarylsulphinyl or heteroarylsulphonyl group, theoxidation of the corresponding compound of the formula I which containsa thio group. (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl,1-oxothiamorpholino or 1,1-dioxothiamorpholino group, wherein X² is agroup of the formula SO, SO₂ C(R⁶)₂SO or C(R⁶)₂SO₂, or wherein Q bears a(1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, phenylsulphinyl,phenylsulphonyl, heteroarylsulphinyl or heteroarylsulphonyl group, theoxidation of the corresponding compound of the formula I which containsa thio group; (l) The reaction of an activated derivative of a compoundof the formula XVIII:

 wherein L is a displaceable group as hereinbefore with a compound ofthe formula XIX: NH(R²)-L¹-T¹(R³)—X¹—Ar-Q  XIX  and, if necessary,forming a pharmaceutically associated salt.
 9. A pharmaceuticalcomposition which comprises an aminoheterocyclic derivative of theformula I or a pharmaceutically acceptable salt thereof as claimed inany one of claims 1 to 7 and a pharmaceutically acceptable carrier. 10.The use of an aminoheterocyclic derivative of the formula I or apharmaceutically acceptable salt thereof as claimed in any one of claims1 to 7 in the production of a medicament for producing anantithrombiotic or anticoagulant effect.
 11. The use of anaminoheterocyclic derivative of the formula I or a pharmaceuticallyacceptable salt thereof as claimed in any one of claims 1 to 7 in theproduction of a medicament for treating coronary artery orcerebro-vascular disease.